Drug releasing biodegradable fiber for delivery of therapeutics

ABSTRACT

The present invention relates to fiber compositions comprising gels or hydrogels. The invention further relates to the composition of a gel or hydrogel loaded biodegradable fiber and methods of fabricating such fibers. The present invention further provides tissue engineering and drug-delivery compositions and methods wherein three-dimensional matrices for growing cells are prepared for in vitro and in vivo use. The invention also relates to methods of manipulating the rate of therapeutic agent release by changing both the biodegradable polymer properties as well as altering the properties of the incorporated gel or hydrogel.

CROSS REFERENCES TO RELATED APPLICATIONS

This application is a continuation-in-part of application Ser. No.09/632,457, filed Aug. 4, 2000 now U.S. Pat. No. 6,596,296, which claimsthe benefit of U.S. Provisional Application No. 60/147,827, filed Aug.6, 1999.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to the field of medicine and tissue engineering,and in particular to drug releasing biodegradable fibers used in thedelivery of therapeutics.

2. Description of Related Art

Tissue engineering is a discipline wherein living cells are used toreplace cells lost as a result of injury, disease, or birth defect in ananimal or human. These replacement cells can be autologous, allogenic,or xenogenic. The field of tissue engineering is a new area of medicineand optimal procedures have yet to be elucidated.

At present, there are several avenues for engineering tissues. Oneavenue is to harvest cells from a healthy donor, preferably from thesame individual, or at least from an appropriate donor of the samespecies, and grow those cells on a scaffold in vitro. This scaffold istypically a three-dimensional polymer network, often composed ofbiodegradable fibers. Cells adherent to the polymer network can thentypically be induced to multiply. This cell filled scaffold can beimplanted into the impaired host with the goal that the cells willperform their physiological function and avoid destruction by the hostimmune system. To this end, it is important that purified cell lines areused, as the introduction of non-self immune cells can up-regulate astrong host immune attack. The difficulty with this approach is thescaffolding must be small, as no cell can survive more than a couplemillimeters away from a source of oxygen and nutrients. Therefore, largescaffolds cannot be used, as the scaffold will not vascularizeadequately in time to save the cells in the interior regions.

In another approach, an empty three-dimensional, biodegradable polymerscaffold is directly implanted in the patient, with the goal of inducingthe correct type of cells from the host's body to migrate into thepolymer scaffold. The benefit is that vascularization can happensimultaneously with migration of cells into the matrix. A major problemis that there is currently no way to ensure that the appropriate celltypes will migrate into the scaffold, and that the mechanical andbiological properties will be maintained to provide the patient'sphysiological need.

In both of the above approaches, the scaffold may be biodegradable,meaning that over time it will break down both chemically andmechanically. As this break down occurs, the cells secrete their ownextracellular matrix, which plays a critical role in cell survival andfunction. In normal tissue, there is an active and dynamic reciprocalexchange between the constitutive cells of the tissue and thesurrounding extracellular matrix. The extracellular matrix provideschemical signals that regulate the morphological properties andphenotypic traits of cells and may induce division, differentiation oreven cell death. In addition, the cells are also constantly rearrangingthe extracellular matrix. Cells both degrade and rebuild theextracellular matrix and secrete chemicals into the matrix to be usedlater by themselves or other cells that may migrate into the area. Ithas also been discovered that the extracellular matrix is one of themost important components in embryological development. Pioneering cellssecrete chemical signals that help following cells differentiate intothe appropriate final phenotype. For example, such chemical signalscause the differentiation of neural crest cells into axons, smoothmuscle cells or neurons.

The integrated relationship between extracellular matrix and tissuecells establishes the extracellular matrix as an important parameter intissue engineering. If cells are desired to behave in a specific manner,then the extracellular matrix must provide the appropriate environmentand appropriate chemical/biological signals to induce that behavior forthat cell type. Currently it is not possible to faithfully reproduce abiologically active extracellular matrix. Consequently, someinvestigators use a biodegradable matrix that enables the cells tocreate their own extracellular matrix as the exogenous matrix degrades.

In the above-described approaches to tissue engineering, a polymerscaffold provides not only the mechanical support, but also thethree-dimensional shape that is desired for the new tissue or organ.Because cells must be close to a source of oxygen and nutrients in orderto survive and function, a major current limitation is that of bloodsupply. Most current methodologies provide no specific means of activelyassisting the incorporation of blood vessels into and throughout thepolymer matrix. This places limitations on the physical size and shapeof the polymer matrix. The only current tissue-engineering device thathas made it into widespread clinical use is artificial skin, which bydefinition is of limited thickness. The present invention providescompositions and methods that promote the directed migration ofappropriate cell types into the engineered extracellular matrix. Bydirecting specific three-dimensional cell migration and functionalpatterns, directed vascularization can be induced, which overcomes thecurrent limitations on the shape and size of polymer implants. It alsoensures that appropriate cell types will be physically located inspecific locations within the matrix. Compositions and methods areprovided to modulate phenotypic expression as a function of both timeand space.

Most of the drug delivery from polymeric drug-loaded vehicles is basedon the following formats: microspheres, nano-particles, foams, films,liposomes, polymeric micelles, or viral packages. There are a number ofinherent disadvantages with respect to the above mentioned formats.Several of the above mentioned drug delivery formats do not remain inplace after they have been implanted. As a result retrieval of theimplant is not possible in the case of an adverse reaction to theimplant. Additionally, these formats display high surface area per unitvolume, which leads to quick drug release times, a feature that isantithetical to the goal of drug delivery. Furthermore, the amount ofdrug that can be loaded into the above mentioned formats is somewhatlimited. Some of these formats cannot be used in conditions which inaddition to drug delivery, also require mechanical support.

The present invention provides a fiber composition that does not possessthe disadvantages of the drug delivery formats known in the prior art.

SUMMARY OF THE INVENTION

The present invention relates to fiber compositions comprising gels orhydrogels. The invention further relates to the composition of a gel orhydrogel loaded biodegradable fiber and methods of fabricating suchfibers. The present invention further provides tissue engineering anddrug-delivery compositions and methods wherein three-dimensionalmatrices for growing cells are prepared for in vitro and in vivo use.The invention also relates to methods of manipulating the rate oftherapeutic agent release by changing both the biodegradable polymerproperties as well as altering the properties of the incorporated gel orhydrogel.

An embodiment of the invention provides a drug delivery compositioncomprising at least one fiber, wherein said fiber comprises a firstcomponent and a second component, and wherein said first component is abiodegradable polymer and said second component is selected from thegroup consisting of a gel and a hydrogel. Another embodiment of theinvention provides a drug delivery composition comprising a fiber,wherein said fiber comprises a first component and a second component,and wherein said first component is a biodegradable polymer and saidsecond component is water, and further wherein said water is present asan inner core. A further embodiment of the invention provides a drugdelivery composition comprising a fiber, wherein said fiber comprises anemulsion consisting essentially of a gel or hydrogel. An embodiment ofthe invention provides drug delivery composition comprising a fiber,wherein said fiber comprises a first component, and wherein said firstcomponent is a gel or hydrogel and further wherein said fiber comprisesa hollow bore. An embodiment of the invention provides a scaffoldcomposition comprising one or more fibers, wherein said fibers comprisea first component and a second component, and wherein said firstcomponent is a biodegradable polymer and said second component isselected from the group consisting of a gel and a hydrogel. Embodimentsof the invention also provide methods of manufacturing the fibers of thepresent invention.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings form part of the present specification and areincluded to further demonstrate certain aspects of the presentinvention. The invention may be better understood by reference to one ormore of these drawings in combination with the detailed description ofspecific embodiments presented herein. The drawings are not intended tolimit the scope of the invention.

FIG. 1A depicts a bicomponent fiber with a water bore (10) and a wallcomprising a hydrophobic polymer (20).

FIG. 1B depicts a bicomponent fiber with a water bore (10), a wallcomprising a hydrophobic polymer (20) and a water emulsion (30).

FIG. 1C depicts a bicomponent fiber with a water bore (10), a wallcomprising a hydrophobic polymer (20), and a gel or hydrogel emulsion(40).

FIG. 1D depicts a bicomponent fiber with a water bore (10), a wallcomprising a hydrophobic polymer (20), and both water and gel orhydrogel emulsions (50).

FIG. 2A depicts a bicomponent fiber with a gel or hydrogel bore (60) anda wall comprising a hydrophobic polymer (20).

FIG. 2B depicts a bicomponent fiber with a gel or hydrogel bore (60), awall comprising a hydrophobic polymer (20), and a water emulsion (30).

FIG. 2C depicts a bicomponent fiber with a gel or hydrogel bore (60), awall comprising a hydrophobic polymer (20), and a gel or hydrogelemulsion (40).

FIG. 2D depicts a bicomponent fiber with a gel or hydrogel bore (60), awall comprising a hydrophobic polymer (20) and both water emulsions andgel or hydrogel emulsions (50).

FIG. 3A depicts a bicomponent fiber with a gel or hydrogel bore (60) anda wall comprising a hydrophobic polymer (20) that comprises a drug (70).

FIG. 3B depicts a bicomponent fiber with a polymer bore (80) surroundedby a gel or hydrogel wall (90).

FIG. 3C depicts a bicomponent fiber with a polymer bore (80) comprisinga water emulsion (30) that is surrounded by a gel or hydrogel wall (90).

FIG. 3D depicts a bicomponent fiber with a polymer bore (80) comprisinga gel or hydrogel emulsion (40) that is surrounded by a gel or hydrogelwall (90).

FIG. 4A depicts a bicomponent fiber with a polymer bore (80) comprisinga water emulsion and a gel or hydrogel emulsion (50) that is surroundedby a gel or hydrogel wall (90).

FIG. 4B depicts a multicomponent fiber with a gel or hydrogel bore (60)surrounded by two hydrophobic polymer walls (20 and 100), with the outerpolymer wall comprising a water emulsion (30) and the inner polymer wallcomprising a gel or hydrogel emulsion (40).

FIG. 4C depicts a monofilament fiber comprising a hydrophobic polymer(100) and a gel or hydrogel emulsion (40).

FIG. 4D depicts a monofilament fiber comprising a hydrophobic polymer(100) and a water emulsion and a gel or hydrogel emulsion (50).

FIG. 5A depicts a bicomponent fiber with a hydrophobic polymer bore(90), and a wall comprising a hydrophobic polymer (20) that comprises agel or hydrogel emulsion (40).

FIG. 5B depicts a bicomponent fiber with a hydrophobic polymer bore (90)and a wall comprising a hydrophobic polymer (20) comprising a wateremulsion and a gel or hydrogel emulsion (50).

FIG. 5C depicts a bicomponent fiber with a hydrophobic polymer bore (90)comprising a water emulsion (30) and a wall comprising a hydrophobicpolymer (20) that comprises a gel or hydrogel emulsion (40).

FIG. 5D depicts a bicomponent fiber with a hydrophobic polymer bore (90)comprising a gel or hydrogel emulsion (40) and a wall comprising ahydrophobic polymer (20) that comprises a gel or hydrogel emulsion (40).

FIG. 6A depicts a bicomponent fiber with a hydrophobic polymer bore (90)comprising a water emulsion and a gel or hydrogel emulsion (50) and awall comprising a hydrophobic polymer (20) that comprises a gel orhydrogel emulsion (40).

FIG. 6B depicts a bicomponent fiber with a hydrophobic polymer bore (90)comprising a water emulsion (30) and a wall comprising a hydrophobicpolymer (20) that comprises a water emulsion and a gel, or hydrogelemulsion (50).

FIG. 6C depicts a bicomponent fiber with a hydrophobic polymer bore (90)comprising a gel or hydrogel emulsion (40) and a wall comprising ahydrophobic polymer (20) comprises a water emulsion and a gel orhydrogel emulsion (50).

FIG. 6D depicts a bicomponent fiber with a hydrophobic polymer bore (90)comprising both water and gel or hydrogel emulsions (50) and a wallcomprising a hydrophobic polymer (20) comprising both water and gel orhydrogel emulsions (50).

FIG. 7 depicts a wet extrusion apparatus used to extrude fibers of theinvention.

FIG. 8 depicts a spinneret used in the present invention.

FIG. 9 depicts a triple apparatus used in the extrusion of fibers of theinvention.

FIG. 10 depicts a triple spinneret used in the manufacture ofmulticomponent fibers.

FIG. 11 depicts the flow of a therpeutic through the walls of anemulsion-loaded fiber.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

An embodiment of the invention provides a drug delivery compositioncomprising at least one fiber, wherein said fiber comprises a firstcomponent and a second component, and wherein said first component is abiodegradable polymer and said second component is selected from thegroup consisting of a gel and a hydrogel. Another embodiment of theinvention provides a drug delivery composition comprising a fiber,wherein said fiber comprises a first component and a second component,and wherein said first component is a biodegradable polymer and saidsecond component is water, and further wherein said water is present asan inner core. A further embodiment of the invention provides a drugdelivery composition comprising a fiber, wherein said fiber comprises anemulsion consisting essentially of a gel or hydrogel. An embodiment ofthe invention provides drug delivery composition comprising a fiber,wherein said fiber comprises a first component, and wherein said firstcomponent is a gel or hydrogel and further wherein said fiber comprisesa hollow bore. An embodiment of the invention provides a scaffoldcomposition comprising one or more fibers, wherein said fibers comprisea first component and a second component, and wherein said firstcomponent is a biodegradable polymer and said second component isselected from the group consisting of a gel and a hydrogel. Embodimentsof the invention also provide methods of manufacturing the fibers of thepresent invention.

An embodiment of the invention provides a bi-component fiber where theinner bore of the fiber, i.e., inside diameter of the fiber, comprises agel or hydrogel and the outer wall of the fiber comprises abiodegradable polymer. As used herein, the term “gel” refers to acolloidal system with at least two phases, one of which forms acontinuous three-dimensional network that acts as an elastic solid. Asused herein, the term “hydrogel” refers to a colloid in which adispersed phase (colloid) is combined with a continuous phase (water) toproduce a viscous jellylike product.

An alternate embodiment of the invention provides the inverse of theabove, i.e. where the outer wall comprises a gel or hydrogel and theinner bore comprises a biodegradable polymer fiber.

Another embodiment of the invention provides a monofilament fiber wherea hydrogel or gel is dispersed randomly throughout the biodegradablepolymer layer(s). This configuration results in distinct phaseseparation where the biodegradable polymer fiber constitutes acontinuous phase and the gel or hydrogel constitutes a disperse phase.As used herein, a “continuous phase” refers to the liquid in a dispersesystem in which solids are suspended or droplets of another liquid aredispersed. As used herein, a “disperse phase” refers to the phase of adisperse system consisting of particles or droplets of one systemdispersed through another system.

In certain embodiments, where the gel or hydrogel concentration is zero,a water-bored fiber is provided i.e., a fiber in which water is presentwithin the inside diameter of the fiber. In this case, water, optionallyin combination with other materials, comprises the inner core of thefiber and the biodegradable polymer fiber comprises the surroundingsheath of the fiber. In an alternate embodiment, the biodegradablepolymer fiber sheath comprises a dispersion of gel or hydrogel. Inanother embodiment, the biodegradable polymer fiber sheath comprises adispersion of water in place of a dispersion of gel or hydrogel. Inother embodiments, the biodegradable polymer fiber sheath comprises adispersion of water together with a dispersion of gel and hydrogel.

In an embodiment of the invention, the above described fibers arecombined with fibers of similar composition. In other embodiments,fibers of dissimilar type and composition are combined.

In an embodiment, a therapeutic agent is incorporated into one or moreof the above described fibers, present individually or in combination.In other embodiments, a drug is incorporated into one or more of theabove described fibers, present individually or in combination.

In certain embodiments of the invention, a layer of a fibercircumscribes a layer of an adjacent inner fiber. The inner fiber isapproximately centered within the outer fiber. In certain embodiments,one or more of the layers of the circumscribed fibers comprise ahydrogel or a gel in the wall of the fiber or in the bore of the fiber.In additional embodiments, a gel or a hydrogel is incorporated as adispersed phase within the biodegradable polymer of one or more layersof the fibers. Additional embodiments of the invention providemulti-layered fibers, where each layer comprises varying compositions ofgels, hydrogels and therapeutic agents. Certain embodiments of theinvention provide fibers comprising more than one kind of therapeuticagent within its one or more layers.

The invention further relates to methods of manipulating the rate oftherapeutic agent release by changing both the biodegradable polymerproperties as well as altering the properties of the incorporated gel orhydrogel. A therapeutic agent-loaded fiber is suitable for implantationin animals, or more preferably in humans as either single strands foruse as a therapeutic agent delivery vehicles, or together with otherfibers (of either similar or different type) for the formation of afiber-based scaffold for use in tissue engineering, wound healing,regenerative medicine, or other medically related applications. Thesefibers may also be used outside the body to create scaffolds for cellculture, tissue culture, or in vitro organogenesis, wherein specificthree-dimensional structures of these fibers may be woven, knitted,braided, used as a non-woven mesh, or maintained as parallel,non-parallel, twisted or random arrays for the creation of complexthree-dimensional scaffolds. As each fiber within said fiber scaffoldmight be loaded with different therapeutic agents, and each with adifferent release kinetics profile, it may be possible to inducespecific cell growth into specific regions of the scaffold. Thisprovides the ability to create complicated three-dimensional biologicalarchitecture by deliberate placement of specific fibers at specificlocations within the fiber scaffold. These three dimensional biologicalstructures may or may not be biomemetic in their design. By the samemeans, it is possible to release different therapeutic agents to onesection of the cell culture, tissue culture, or organoid than to anotherwithin the same sample.

This type of complex three-dimensional fiber scaffold may also beimplanted into an animal, or a human to induce specific biologicalresponses at different locations within said fiber scaffold. This isaccomplished by designing the fiber scaffold such that fibers withspecific therapeutic agents and specific release profiles are placed atspecific locations within the scaffold. This enables the control of bothtemporal and spatial therapeutic agent delivery from the fiber scaffold.

“Defined nonhomogeneous pattern” in the context of the currentapplication means the incorporation of specific fibers into a scaffoldmatrix such that a desired three-dimensional distribution of one or moretherapeutic agents within the scaffold matrix is achieved. Thedistribution of therapeutic agents within the fibers, and possiblywithin their centers, controls the subsequent spatial distributionwithin the interstitial medium of the matrix scaffold following releaseof the agents from the polymer fibers. In this way, the spatial contoursof desired concentration gradients can be created within the threedimensional scaffold structure and in the immediate surroundings of thescaffold matrix. Temporal distribution is controlled by the polymercomposition and gel or hydrogel composition of the fiber and by the useof multi-layers within a fiber.

One aspect of the present invention is a biocompatible implantcomposition comprising a scaffold of biodegradable polymer fibers. Invarious embodiments of the present invention, the distance between thefibers may be about 20 microns, about 70 microns, about 90 microns,about 100 microns, about 120 microns, about 140 microns, about 160microns, about 180 microns, about 200 microns, about 220 microns, about240 microns, about 260 microns, about 280 microns, about 300 microns,about 320 microns, about 340 microns, about 360 microns, about 380microns, about 400 microns, about 450 microns or about 500 microns. Invarious embodiments the distance between the fibers may be less than 50microns or greater than 500 microns.

Additionally, it is envisioned that in various embodiments of theinvention, the fibers will have a diameter of about 20 microns, about 40microns, about 60 microns, about 80 microns, about 100 microns, about120 microns, about 140 microns, about 160 microns, about 180 microns,about 200 microns, about 220 microns, about 240 microns, about 260microns, about 280 microns, about 300 microns, about 320 microns, about340 microns, about 360 microns, about 380 microns, about 400 microns,about 450 microns or about 500 microns (including intermediate lengths).In various embodiments the diameter of the fibers may be less than about20 microns or greater than about 500 microns. Additionally, large fiberswith diameters up to 3.5 cm are envisioned for certain embodiments.Preferably, the diameter of the fibers will be from about 60 microns toabout 500 microns.

In another embodiment of the present invention, the fibers or a subsetof fibers, contain one or more therapeutic agents such that theconcentration of the therapeutic agent or agents varies along thelongitudinal axis of the fibers or subset of fibers. The concentrationof the active agent or agents may vary linearly, exponentially or in anydesired fashion, as a function of distance along the longitudinal axisof a fiber. The variation may be monodirectional, that is, the contentof one or more therapeutic agents decreases from the first end of thefibers or subset of the fibers to the second end of the fibers or subsetof the fibers. The content may also vary in a bidirection fashion, thatis, the content of the therapeutic agent or agents increases from thefirst ends of the fibers or subset of the fibers to a maximum and thendecreases towards the second ends of the fibers or subset of the fibers.

In certain embodiments of the present invention, a subset of fiberscomprising the scaffold may contain no therapeutic agent. For fibersthat contain one or more therapeutic agents, the agent or agents mayinclude: a growth factor, an immunodulator, a compound that promotesangiogenesis, a compound that inhibits angiogenesis, ananti-inflammatory compound, an antibiotic, a cytokine, ananti-coagulation agent, a procoagulation agent, a chemotactic agent,agents that promotes apoptosis, an agent that inhibits apoptosis, amitogenic agent, a radioactive agent, a contrast agent for imagingstudies, a viral vector, a polynucleotide, therapeutic genes, DNA, RNA,a polypeptide, a glycosaminoglycan, a carbohydrate, a glycoprotein. Thetherapeutic agents may also include those drugs that are to beadministered for long-term maintenance to patients such ascardiovascular drugs, including blood pressure, pacing, anti-arrhythmia,beta-blocking drugs, and calcium channel based drugs. Therapeutic agentsof the present invention also include anti-tremor and other drugs forepilepsy or other movement disorders. These agents may also includelong-term medications such as contraceptives and fertility drugs. Theycould comprise neurologic agents such as dopamine and related drugs aswell as psychological or other behavioral drugs. The therapeutic agentsmay also include chemical scavengers such as chelators, antioxidants andnutritional agents. Wherein the therapeutic agent promotes angiogenesis,that agent may be vascular endothelial growth factor. The therapeuticagents may be synthetic or natural drugs, proteins, DNA, RNA, or cells(genetically altered or not). As used in the specification and claims,following long-standing patent law practice, the terms “a” and “an,”when used in conjunction with the word “comprising” or “including” meansone or more.

In general, the present invention contemplates the use of any drugincorporated in the biodegradable polymer fibers of the invention. Theword “drug” as used herein is defined as a chemical capable ofadministration to an organism, which modifies or alters the organism'sphysiology. More preferably the word “drug” as used herein is defined asany substance intended for use in the treatment or prevention ofdisease. Drug includes synthetic and naturally occurring toxins andbioaffecting substances as well as recognized pharmaceuticals, such asthose listed in “The Physicians Desk Reference,” 471st edition, pages101–321; “Goodman and Gilman's The Pharmacological Basis ofTherapeutics” 8th Edition (1990), pages 84–1614 and 1655–1715; and “TheUnited States Pharmacopela, The National Formulary”, USP XXII NF XVII(1990), the compounds of these references being herein incorporated byreference. The term “drug” also includes compounds that have theindicated properties that are not yet discovered or available in theU.S. The term “drug” includes pro-active, activated, and metabolizedforms of drugs. Tissue stimulating factors are also included such as:dimers of Platelet Derived Growth Factor (PDGF), insulin-like growthfactor-1 (IGF-1), IGF-2, basic Fibroblast Growth Factor (bFGF), acidicFGF, Vascular Endothelial Cell Growth Factor (VEGF), Nerve Growth Factor(NGF), Neurotrophic Factor 3 (NT-3), Neurotrophic Factor 4 (NT-4), BrainDerived Neurotrophic Factor (BDNF), Endothelial Growth Factor (EGF),Insulin, Interleukin 1 (II-1), Tumor Necrosis Factor alpha (TNFα.),Connective Tissue Growth Factor (CTGF), Transforming Growth Factor alpha(TGFα), and all other growth factors and cytokines, as well aspara-thyroid hormone (PTH), prostaglandin such as Prostaglandin E-1 andProstaglandin E-2, Macrophage Colony Stimulating Factor (MCSF), andcorticosteroids such as dexamethasone, prednisolone, and corticosterone.

The present invention also contemplates the use of hydrogel formingmaterial within the core of the fibers. Hydrogels are structurallystable, synthetic polymer or biopolymer matrices that are highlyhydrated. These materials may absorb up to thousands of times theirweight in water, (Hoffman, A. S., Advanced Drug delivery Reviews, 43(2000), 3–12). Hydrogels can be classified into two broad categories:reversible or physical and irreversible or chemical. The networks inphysical gels are held together by molecular entanglements and/orsecondary forces including ionic, H-bonding or hydrophobic forces.Physical hydrogels are characterized by significant changes in therheological properties as a function of temperature, ionicconcentration, and dilution. Chemical gels, also called permanent gels,are characterized by chemically crosslinked networks. When crosslinked,these gels reach an equilibrium swelling level in aqueous solutionswhich depends mainly on the crosslink density.

The preparation of hydrogels can be achieved by a variety of methodswell known to those of ordinary skill in the art. Physical gels can beformed by: heating or cooling certain polymer solutions (cool agarose,for example), using freeze-thaw cycles to form polymer microcrystals,reducing the solution pH to form a H-bonded gel between two differentpolymers in the same aqueous solution, mixing solutions of a polyanionand a polycation to form a complex coacervate gel, gelling apolyelectrolyte solution with a multivalent ion of opposite charge,reticulation of linear polymers, grafting of synthetic polymers ontonaturally occurring macromolecules, and chelation of polycations(Hoffman, A. S., Advanced Drug delivery Reviews, 43 (2000), 3–12).Chemical gels can be created by crosslinking polymers in the solid stateor in solution with radiation, chemical crosslinkers likeglutaraldehyde, or multifunctional reactive compounds. They can also bemade by copolymerizing a monomer and a crosslinker in solution,copolymerizing a monomer and a multifunctional macromer, polymerizing amonomer within a different solid polymer to form an IPN gel, orchemically converting a hydrophobic polymer to a hydrogel (Hoffman, A.S., Advanced Drug delivery Reviews, 43 (2000), 3–12); Hennick, W. F. andvan Nostrum, C. F., Advanced Drug Delivery Reviews, 54 (2002), 13–26.

The present invention contemplates the use of hydrogel precursormaterials and non-gelling proteins and polysaccharides within the boreof the fibers. Hydrogel precursor materials are the same materials asthose that form hydrogels, but they are not exposed to the agents orconditions that normally gel the materials, or can be other proteins andpolysaccharides that form gels but not hydrogels. For example, alginatesalts, such as sodium alginate, are gelled in the presence of divalentcations, such as calcium, while other materials create hydrogels via achange in pH or temperature. Certain embodiments of the inventioncomprise the use of precursor materials that are never gelled. Otherembodiments of the invention comprise the use of precursor materials inthe fabrication process that later may form gels or hydrogels. Theformation of gels or hydrogels in the fiber layer may take place as apart of the fiber fabrication process, after the fiber has beenfabricated, or after the application of an appropriate type of externalstimuli, including placing the fiber in vitro or in vivo. The terms“gel” or “hydrogel” as used herein is intended to include the formed gelor hydrogel as well as the appropriate precursor molecules involved inthe formation of gels and hydrogels.

The biodegradable polymer used for fiber construction may be a singlepolymer or a co-polymer or blend of polymers and may comprisepoly(L-lactic acid), poly(DL-lactic acid), polycaprolactone,poly(glycolic acid), polyanhydride, or natural polymers or polypeptides,such as reconstituted collagen or spider silk and polysaccharides.

The fibers of the claimed invention are manufactured using wet ordry/wet (dry jet wet) spinning. Each method affects the final propertiesof the fiber being constructed. Wet spinning is a process in which apolymeric material is extruded into a liquid bath containing acoagulant. The coagulant is typically comprised of a non-solvent for thepolymer that is miscible with the solvent in the polymer solution, butit can also contain a solvent/non-solvent mixture. In dry jet wetspinning, the polymer solution is first exposed to an air gap beforeentering the coagulation bath.

In an embodiment of the invention, the fiber comprises a plurality ofco-axial layers of biodegradable polymers. The drug delivery fiber ofthe present invention may be implanted into many sites in the bodyincluding dermal tissues, cardiac tissue, soft tissues, nerves, bones,and the eye. Ocular implantation has particular use for treatment ofcataracts, diabetically induced proliferative retinopathy andnon-proliferative retinopathy, glaucoma, and macular degeneration.

A further aspect of the present invention is a method of producing afiber-scaffold for preparing an implant capable of controlling thespatial and temporal concentration of one or more therapeutic agents.This method generally comprises forming biodegradable polymer fibersinto a three dimensional fiber-scaffold. The biodegradable polymerfibers contain one or more therapeutic agents. The therapeutic agent oragents are distributed in the fiber-scaffold in a defined nonhomogeneouspattern.

In certain embodiments of the invention, gels and hydrogels comprised inthe fiber layers may exist at infinitely dilute concentrations, i.e.,the concentration of gel or hydrogel is zero, and water is used with orwithout other substances and/or active agents, including therapeuticagents, in place of the gel or hydrogel.

In one embodiment of this invention, the preferred material for thehydrogel contained in the bore of the fiber will be alginate or modifiedalginate material. Alginate molecules are comprised of (1–4)-linkedβ-D-mannuronic acid (M units) and (α-L-guluronic acid (G units)monomers, which vary in proportion and sequential distribution along thepolymer chain. Alginate polysaccharides are polyelectrolyte systems thathave a strong affinity for divalent cations (e.g. Ca²⁺, Sr²⁺, Ba²⁺) andform stable hydrogels when exposed to these molecules. The biodegradablepolymer is poly(L-lactic acid) (PLLA). In an embodiment, the alginate iscontained as the inner core and the PLLA is the outer sheath. Theconcentration of alginate is in the range of 0.25 w/v % to 100 w/v %(i.e., g/100 ml water), preferably in the range of 0.75 w/v % to 20 w/v%, and most preferably at a concentration of 1 w/v %. The source andcomposition of alginate directly affects its usable concentration.

In another embodiment of this invention, the PLLA sheath surrounding theinner gel or hydrogel core comprises a cocktail of PLLA polymers ofdifferent molecular weights as a means of increasing the degradationrate. The proportions of the PLLA polymers and the range of the polymermolecular weights can vary. In an exemplary embodiment, the polymercocktail comprises 80% by weight of a PLLA polymer of Mw=100,000Daltons; 15% by weight of a polymer of Mw=2,000 Daltons; and 5% byweight of a polymer Mw=300,000 Daltons.

In another embodiment of the invention, the PLLA sheath surrounding theinner gel or hydrogel core is comprised of two phases, a continuousphase comprising a biodegradable polymer and a dispersed phasecomprising an aqueous phase stabilized by a surfactant. The aqueousphase may optionally comprise therapeutic agents. The amount of thedispersed phase ranges from about 0% to about 85% by weight relative tothe weight of the fiber. In a preferred embodiment the amount of thedispersed phase ranges from about 33% to about 50% by weight relative tothe weight of the fiber. As the ratio of the dispersed phase increases,so does the rate of degradation of the polymer. This leads to increasedrelease rates of loaded therapeutic agents.

In an embodiment of this invention, agents that are designed to degradethe gel or hydrogel are loaded into the dispersed aqueous phase of thebiodegradable polymer component of the fiber (as described above). Thisagent is released into the gel or hydrogel slowly over time to breakdown the gel or hydrogel. This increases therapeutic agent releaserates. In addition, many of the potential gels and hydrogels are notdirectly biodegradable within animals, or more especially humans.Therefore, this planned degradation helps the body to eliminate the gelsor hydrogels when they are no longer needed.

In an embodiment, the alginate is gelled internally by the addition ofgelling agents added directly to the alginate solution. Typical gellingagents include calcium chloride, calcium carbonate, calcium-EDTA(Ethylene Diamine Tetracetic Acid), or other compounds containingbivalent cations that are well known to those skilled in the art. Theconcentration of the gelation agent ranges from about 5 mM to about 100mM, more preferably from about 12 mM to about 50 mM, and most preferablyfrom about 15 mM to 30 mM. The range chosen is determined by desiredhydrogel properties. If not readily soluble at neutral pH, the gellingagent is typically activated by a drop in pH of the solution. Thisacidification can be achieved through a number of acids or lactones.This list includes, but is not limited to, citric acid, hydrochloricacid, D-glucono-delta-lactone, and glacial acetic acid.

In another embodiment, the gel or hydrogel is gelled externally byincorporating the gelling agent source into the biodegradable fiber.Alternately, the gelling agent source is added to a water phase that isloaded into one or more layers of the biodegradable polymer. In thisway, the gelling agent is slowly released into the gel or hydrogel asthe fiber degrades. In certain embodiments, as the fiber degrades andbecomes weaker and more porous, the gel becomes more tightlycross-linked. In this way, it may be possible to continuously alter therelease rate as the fiber degrades. Release rates tend to increase asthe polymer becomes more porous, in this case, this trend would beoffset by the gel becoming more tightly cross-linked, hence retardingrelease rates through the gel or hydrogel as the fiber degrades.

In another embodiment, the gelling agent is soluble in the polymersolvent and is mixed with the polymer solution at the time of fiberfabrication. In this embodiment, rather than the gelling agent beingmaintained in an aqueous phase, it is molecularly mixed with thepolymer. The same net effect of releasing the gelling agent into the gelor hydrogel slowly as the fiber degrades. This embodiment allows the useof organically soluble sources of gelling agents.

In another embodiment, the gelation agents are carried within thealginate solution that are activated over time, such as withinlipospheres, microspheres, nanoparticles or other encapsulants that areactivated later. These may be slowly activated over time, orpurposefully activated by some external event. This will result in thegel either being strengthened, or maintained over time.

In another embodiment of the invention, the gel or hydrogel is theexterior sheath and the biodegradable polymer is the interior core. Inthis embodiment the gelling agent is in the coagulating bath, whichwould be an external gelation.

The present invention provides compositions and methods to createsingle, drug releasing fibers as well as the composition and methods tocreate a heterogeneous, woven, knitted, braided, non-woven, twisted,parallel array or random three-dimensional fiber scaffold for growingcells in tissue engineering applications. These scaffolds can be used invitro and in vivo, and due to their heterogeneity can create bothspatial and temporal distributions of therapeutic agents. In thisinvention, therapeutic agents may include drugs, proteins, peptides,mono- and di-saccharides, polysaccharides, glycoproteins, DNA, RNA,viruses, or other biological molecules of interest. The term therapeuticagent in this invention also includes radioactive materials used to helpdestroy harmful tissues such as tumors in the local area, or to inhibitgrowth of healthy tissues, such as in current stent applications; ormarkers to be used in imaging studies.

A. Three Dimensional Fiber Scaffolds

To create the heterogeneous scaffolds of the present invention, thetherapeutic agents are encapsulated into individual fibers of the matrixby methods to be described herein. The therapeutic agents are releasedfrom each individual fiber slowly, and in a controlled manner. The fiberformat has many advantages as a drug delivery platform over other slowdrug-releasing agents known to those familiar in the art such asmicrospheres, porous plugs or patches. The primary advantage of fibersis that they can provide complex three-dimensional woven, or non-wovenscaffolding, with or without patterning, to allow cells to attach,spread, differentiate, and mature into appropriately functioning cells.Because they can form patterns, a “smart scaffold” can be produced toinduce cells of specific types to migrate to specific regions of thescaffold due to specific chemotactic factors being released. Thisscaffold mimics the function of the extracellular matrix material bothduring embryological development and in post-embryological tissues.Additionally, filaments could be formed into a unique scaffold thatprovides a growth substrate for tissue repair or reconstruction that isnot reminiscent of a natural like structure.

Because of the ability to weave patterns to induce appropriate celltypes into specific regions, it is possible to incorporate strands thatwill induce the formation of blood vessels into the fabric. This may beaccomplished by providing fibers that release growth factors such asvascular endothelial growth factor (VEGF). By appropriate spacing ofVEGF containing-fibers into the weave pattern, large tissues may beengineered, and the cells in such tissues can be provided with asufficient blood supply and thereby receive oxygen and nutrients andenable the removal of waste products.

Fibers also have the advantage of providing the body with short termmechanical support in such applications as stents, wherein the polymerfiber can maintain the lumen of any tubular body, such as arteries,veins, ducts (e.g. bile duct, ureter, urethra, trachea, etc.), organs ofthe digestive track such as esophagus, intestine, colon, and connectivetissue such as tendons, ligaments, muscle and bone. The fibers provide auseful structure to support mechanical strength or tension during thehealing process. Fibers may also be useful to promote neuralregeneration or reconstruction of nerves or spinal cord.

B. Fiber Formats

There are a large number of combinations and variations within the scopeof this invention. This invention covers gel or hydrogel combinationswith a biodegradable polymer fiber in a multi-layer, multi-componentformat, where each layer is fully contained within the next outer layer,and the inner layer is generally centered within the outer layer. Theselayers can be comprised of different gels or hydrogels, or differentbiodegradable polymers.

This invention also includes the use of gels or hydrogels as a dispersedphase within biodegradable polymer layer, wherein the continuous phaseis the biodegradable polymer phase. The dispersed phase may bestabilized by either an internal or external surfactant.

In the case of the dispersed gel or hydrogel within the biodegradablepolymer layer, and in the case of the gel or hydrogel layer beinginterior to a biodegradable polymer layer, an allowable special case isthat the concentration of the hydrogel is zero. This means that watermay be used (with or without the inclusion of other substances) in theplace of the gel or hydrogel.

As an additional special case, it may be possible for the polymerconcentration in the innermost core to be zero, in which case thesolvent normally used with the polymer is replaced by a non-solvent. Inthis case, the non-solvent core acts as an internal coagulating bath.The result is that a hollow fiber is created. This special case canoccur with or without a gel or hydrogel exterior to the biodegradablepolymer layer(s) and with or without a dispersed gel, hydrogel or waterphase within the biodegradable polymer layer(s).

This leads to a large number of potential combinations. The basic typesare external biodegradable polymer with internal gel or hydrogel, andthe inverse design, i.e. gel or hydrogel external with the biodegradablepolymer as the internal core. In each of these combinations, thebiodegradable polymer layer may or may not have a dispersed water, gelor hydrogel phase. Another case is a monofilament fiber with a gel orhydrogel dispersed phase.

C. Release Kinetics of Individual Fibers

Further, there are various means for controlling the release kinetics ofthe therapeutic agent, thus temporally controlling the release of thetherapeutic agent. The following discussion will pertain only to thefiber format wherein the polymer sheath surrounds an inner core of gelor hydrogel. The first point of control for the polymer is to mix lowmolecular weight polymer in with the higher molecular weight, fiberforming polymers. In this way, the lower molecular weight component isable to rapidly degrade and diffuse from the fiber, making the fibermore porous. This makes the interior therapeutic agents within the gelor hydrogel more accessible. A second means of accelerating the releaserate of the fiber is to create a bi-phasic fiber, wherein the continuousphase is the biodegradable polymer, and the dispersed phase is aqueouspockets that are stabilized by a surfactant. As the concentration of thedispersed phase increases, a pathway is created from the outside to theinner gel or hydrogel where the only polymer that must be degraded isbetween the various pockets of the dispersed aqueous phase. This has theeffect of leaving much less polymer to degrade to connect the gel orhydrogel to the outside world, thus accelerating the release of thetherapeutic agent. It is also possible for this dispersed aqueous phaseto contain the same or a different drug or therapeutic agent. In thiscase, the drug or therapeutic agent in the dispersed aqueous phase willbe released first, followed by the release of the therapeutic agent inthe gel or hydrogel. To alter the release kinetics of the drug ortherapeutic agent in the polymer fiber wall, it is possible to slightlyadapt the above description such that the dispersed phase is now a gelor hydrogel as opposed to being aqueous. In this case, the fluid pathwayshortening exists as in the case of an aqueous dispersed phase; however,the connecting pathway must now go through pockets of gel or hydrogel,wherein the diffusion of the therapeutic agent is retarded compared to apurely aqueous pathway. The degree to which the diffusion is retarded isa function of the type of gel or hydrogel, the type and degree ofcross-linking, and the concentration of the gel or hydrogel. All ofthese parameters are within the control of the entity forming the fiber.It is also possible to control the concentration of the dispersedaqueous or gel phase within the biodegradable polymer as a function ofdistance along the long axis of the fiber. By this means, it is possibleto have different release kinetics at one end of the fiber than at theother, with a defined gradient of release kinetics down the length ofthe fiber. This change in release kinetics may or may not be combinedwith a gradient of therapeutic agent concentration. By the same means,it is possible to have the content of the disperse phase vary as afunction of distance down the polymer fiber such that at one end thedispersed phase would be for example purely aqueous and at the secondend of the fiber, the dispersed phase could be a gel or hydrogel. Othergradients are also possible including varying concentrations of the gelwithin the disperse phase. Thus a great deal of control is available onthe release kinetics of the fiber. Aside from these changes in thepolymer wall of the fiber, it is also possible to control the releasekinetics from this fiber by altering the type, concentration, and degreeof cross-linking within the gel or hydrogel in the core of the fiber,which contains a therapeutic agent.

The ability to dynamically change the release kinetics of the gel orhydrogel being loaded into the core or as a dispersed phase within abiodegradable polymer fiber over the course of the drug delivery periodconstitutes an important aspect of the invention. This affords uniqueopportunities that are not possible to be present in other forms of drugdelivery from gels or hydrogels. The first means of control availablebecause of the gel being loaded into a biodegradable polymer fiber isthe ability of this fiber to release agents known to cross link the gel.In this way, over time, the cross-linking density of the gel actuallyincreases, which will retard the release of the therapeutic agent. Thisrelease of the cross linking agent from the biodegradable polymer fibersheath is itself controllable by means outlined above, i.e. using acocktail of molecular weights, or changing the concentration of thedispersed aqueous phase. As a special case of the biodegradable polymerfiber sheath is a multi-layer, and multi-component biodegradable polymersheath. This allows the creation of directional specificity, as well aschanges in the release kinetics from each layer of the biodegradablepolymer fiber sheath. For example, consider the case of two layers ofbiodegradable polymer fiber in the sheath. The innermost layer couldcontain agents that act to cross link the gel or hydrogel core of thefiber, and this layer could be composed of a biodegradable polymer thathas a rapid degradation rate. Further, this layer could contain a highdegree of dispersed aqueous phase. In this same example, the outermostlayer may be composed of a different biodegradable polymer with adifferent degradation rate, and a different concentration of dispersedaqueous (or gel or hydrogel) dispersed phase, including zero. Thisexample would create a situation where the cross-linking agent would bedelivered inwardly to the gel or hydrogel in the core of the fiber overtime, thus creating a situation wherein the diffusion coefficient of thetherapeutic agent loaded into the gel or hydrogel in the core of thefiber decreases over time.

Another special case is where the polymer fiber contains agents thatdegrade the gel or hydrogel in the core of the fiber. Using the samelogic as explained above, this too creates a situation where thediffusion coefficient of the therapeutic agent in the gel or hydrogel inthe core or dispersed within the fiber changes continuously over time.In this case, however, the diffusion rate increases over time. Thisparticular case also has the advantage that the body of the animal orpreferably the human into which the fiber is implanted may not have thespecific enzymes or other chemical conditions required to degrade thegel or hydrogel. In this case, loading appropriate degradation agentsinto the wall of the fiber allows the degradation of the gel orhydrogel, and thus aids the clearance of the gel or hydrogel from thehost. Again, as described above, the release of the degradation agentsis largely controllable by changing properties of the biodegradablepolymer layers in the sheath of the fiber.

By these methods, it is seen that the release kinetics of thetherapeutic agent from a gel or hydrogel core or dispersed in a sheathof biodegradable polymer fiber is alterable by virtue of the presence ofbiodegradable polymer sheath.

In the case where the gel or hydrogel is the exterior layer and thebiodegradable polymer is the core of the fiber. In this case thebiodegradable polymer core may consist of one or more multi-componentlayers as described above, and again each layer may contain a differentconcentration of dispersed aqueous or gel or hydrogel phase, which mayor may not themselves carry therapeutic agents. The overall release oftherapeutic agent(s) from the fiber is controlled by the location of thetherapeutic agents, either in the gel or hydrogel exterior, or withinthe biodegradable polymer core or both. By the same means as describedabove, the exterior gel or hydrogel release kinetics may be altered bythe release of cross-linking, or degrading agents from the biodegradablepolymer fiber core. As these agents are released from the biodegradablepolymer fiber core, they will alter the properties of the exterior gelor hydrogel, thus decreasing or increasing the diffusion of thetherapeutic agent from the exterior gel or hydrogel. For any therapeuticagent(s) within the biodegradable polymer core, the release of theseagents is controlled on two levels. First, as explained above the typeand molecular weight distribution of the polymer itself changes therelease kinetics, as well known to those skilled in the art. In additionto this, the concentration of any dispersed aqueous or gel or hydrogelphase will alter the release from the biodegradable polymer. However, asthe gel or hydrogel is surrounding the biodegradable fiber, alltherapeutic agents within the biodegradable polymer must diffuse throughthe gel or hydrogel. Therefore, any changes to the diffusion of thetherapeutic agent(s) through the gel or hydrogel also directly affectthe release of any therapeutic agents within the core of the fiber.Therefore, in this case, one can change the release kinetics of thefiber by altering both the gel and the biodegradable polymer segments.

If the dispersed phase is a gel or hydrogel that also contains thetherapeutic agent, then the release of that therapeutic agent iscontrollable by the same means of choice of biodegradable polymer,molecular weight distribution, and concentration of the dispersed phase.In addition, the properties of the gel or hydrogel also alter therelease of the therapeutic agent from the dispersed phase within themonofilament fiber.

D. Biodegradable Polymers

Preferred polymers for use in the present invention include singlepolymer, co-polymer or a blend of polymers of poly(L-lactic acid),poly(DL-lactic acid), polycaprolactone, poly(glycolic acid) orpolyanhydride. Naturally occurring polymers may also be used such asreconstituted collagen or natural silks. Those of skill in the art willunderstand that these polymers are just examples of a class ofbiodegradable polymer matrices that may be used in this invention.Further biodegradable matrices include polyanhydrides, polyorthoesters,and poly(amino acids) (Peppas and Langer, 1994). Any such matrix may beutilized to fabricate a biodegradable polymer matrix with controlledproperties for use in this invention. A non-exhaustive list ofbiodegradable polymers that produce non-toxic degradation products arelisted in Table 1.

TABLE 1 Biodegradable polymers Synthetic Polypeptides PolydepsipeptidesNylon-2/nylon-6 copolyamides Aliphatic polyesters Poly(glycolic acid)(PGA) and copolymers Poly(lactic acid) (PLA) and copolymer Poly(alkylenesuccinates) Poly(hydroxy butyrate) (PHB) Poly(butylene diglycolate)Poly(ε-caprolactone) and copolymers Polydihydropyrans PolyphosphazenesPoly(ortho ester) Poly(cyano acrylates) Natural Modified polysaccharidescellulose, starch, chitin Modified proteins collagen, fibrin Adaptedfrom Wong and Mooney, 1997.

E. Types of Gels and Hydrogels

In simple terms, a gel is a liquid system that acts like a solid. Moretechnically defined, a gel is a colloidal system with at least twophases, one of which forms a continuous three-dimensional network thatacts as an elastic solid. Gel formation through physical, molecular, orchemical association results in an infinite molecular weight for thesystem. The viscoelastic material formed has a storage modulus, G′, thatis greater than the loss modulus, G″, and both G′ and G″ are almostindependent of frequency. [E. R. Morris, Polysaccharide solutionproperties: origin, rheological characterization and implications forfood systems, Frontiers in Carbohydrate Research 1: Food Applications(R. P. Millane, J. N. BeMiller, and R. Chandrasekaran, eds.), Elsevier,London, 1989, p. 132.] The storage modulus characterizes the rigidity ofthe sample, while the loss modulus characterizes the resistance of thesample to flow. [Damodaran, Srinivasan, Food Proteins and TheirApplications, Food Science and Technology (Marcel Dekker, Inc.); NewYork Marcel Dekker, Inc., 1997.] Examples are polymer solutions,micellar solutions, microemulsions and, in more recent years, the fieldhas been extended with the large number of organic solvents that aregelled by the presence of small organic molecules at very lowconcentrations.

A hydrogel is defined as a colloid in which the disperse phase (thecolloid) has combined with the continuous phase (water) to produce aviscous jellylike product. [Dictionary of Chemical Terms, 4th Ed.,McGraw Hill (1989)]. Hydrogels are able to swell rapidly in excess waterand retain large volumes of water in their swollen structures. Thepolymeric material comprising the hydrogel can absorb more than 20% ofits weight in water, though formed hydrogels are insoluble in water andthey maintain three-dimensional networks. [Amidon, Gordon L., TransportProcesses in Pharmaceutical Systems, Drugs and the PharmaceuticalSciences; v. 102 New York Marcel Dekker, Inc., 2000]. They are usuallymade of hydrophilic polymer molecules crosslinked either by chemicalbonds or by other cohesion forces such as ionic interaction, hydrogenbonding, or hydrophobic interaction. [J. I. Kroschwitz, ConciseEncyclopedia of Polymer Science and Engineering, New York, Wiley, XXIX,p 1341, 1990.]

Hydrogels are -elastic solids in the sense that there exists aremembered reference configuration to which the system returns evenafter being deformed for a very long time.

An organogel is defined as an organic phase with an interlaced polymericcomponent. Preferred solvents include non-toxic organic solventsincluding, but not limited to, dimethyl sulfoxide (DMSO), mineral oilsand vegetable oils. The term “organogel” was initially used to describea specific concept of gelation, by a gelatin solution, of a water-in-oilinverse microemulsion (see Luisi et al. Colloid & Polymer Science, 1990,vol. 268, p. 356–374). The term has recently been extended to gelledsystems comprising two immiscible phases (water in oil) stabilized inlecithin enriched with phosphatidylcholine and usually hydrogenated (seeWilliman et al. Journal of Pharmaceutical Sciences, 1992, vol. 81, p.871–874, and Schchipunov et al., Colloid Journal, 1995, vol. 57, p.556–560). These emulsions have a lamellar phase and are in the form ofgels even in the absence of gelling agents, hence the name organogels,which denotes this type of emulsion irrespective of the orientation ofthe emulsion (Water-in-Oil or Oil-in-Water).

The types of gel materials used in the present invention includepolysaccharides, including but not be limited to, amylose, amylopectin,glycogen, cellulose, hyaluronate, chondroitin, heparin, dextrin, inulin,mannan, chitin, galactose, guar gum, carrageenan, agar, furcellaran,xanthan gum, other hydrocolloid gums, pectin, locust bean gum, acacia,ghatti gum, pentosan, arabinogalactan, synthetic derivatives thereof,and mixtures thereof

Examples of materials which can form hydrogels include natural andsynthetic polysaccharides and other natural and synthetic polymers andtheir derivatives, and combinations of these. Suitable polysaccharidesand polymers include but are not limited to: amylose, amylopectin,glycogen, cellulose, hyaluronic acid, chondroitin sulfate, heparin,dextrin, inulin, mannan, chitin, galactose, guar gum, carrageenan, agar,furcellaran, xanthan gum, other hydrocolloid gums, pectic acid andpectin, locust bean gum, acacia, ghatti gum, pentosan, arabinogalactan,alginates and alginate derivatives, gellan, gellan gum, glucose,collagen (and gelatin), cellulose, carboxymethylcellulose,hydroxymethylcellulose, hydroxypropylmethylcellulose, methylcellulose,and methoxycellulose, fibrin, xanthan and xanthan gum, agarose, chitosan(polycationic polysaccharide polymers), albumin, human gamma globulin,pullulan, carrageenan (polyanionic polysaccharide polymers), dextrin,dextran, dextran sulfate, keratin, inulin, dextrose, amylose, glycogen,amylopectin, polylysine and other polyamino acids, polyesters such aspolyhydroxybutyrate and polyphosphazines, poly(vinyl alcohols),poly(alkylene oxides) particularly poly(ethylene oxides), polyethyleneglycol (including PEO-PPO-PEO and the like block copolymers likePluronics®), poly(allylamines) (PAM), poly(acrylates), modified styrenepolymers, pluronic polyols, polyoxamers, polypropylenes, polyurethanes,poly(uronic acids), polyvinyl chloride, poly(vinylpyrrolidone) andcopolymers, graft copolymers, synthetic derivatives, blends and othermixtures of the above. Polysaccharides are the preferred polymers forthis invention. Alginate, for example, is biocompatible, non-cytotoxic,non-carcinogenic, non-inflammatory, and non-immunogenic, and, therefore,a good candidate for use.

F. Types of Polymeric Materials

Exemplary natural polymers include naturally occurring polysaccharides,such as, for example, arabinans, fructans, fucans, galactans,galacturonans, glucans, mannans, xylans (such as, for example, inulin),levan, fucoidan, carrageenan, galatocarolose, pectic acid, pectins,including amylose, pullulan, glycogen, amylopectin, cellulose, dextran,dextrin, dextrose, glucose, polyglucose, polydextrose, pustulan, chitin,agarose, keratin, chondroitin, dermatan, hyaluronic acid, alginic acid,xanthan gum, starch and various other natural homopolymer orheteropolymers, such as those containing one or more of the followingaldoses, ketoses, acids or amines: erythrose, threose, ribose,arabinose, xylose, lyxose, allose, altrose, glucose, dextrose, mannose,gulose, idose, galactose, talose, erythrulose, ribulose, xylulose,psicose, fructose, sorbose, tagatose, mannitol, sorbitol, lactose,sucrose, trehalose, maltose, cellobiose, glycine, serine, threonine,cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid,lysine, arginine, histidine, glucuronic acid, gluconic acid, glucaricacid, galacturonic acid, mannuronic acid, glucosamine, galactosamine,and neuraminic acid, and naturally occurring derivatives thereofAccordingly, suitable polymers include, for example, proteins, such asalbumin.

Exemplary semi-synthetic polymers include carboxymethylcellulose,hydroxymethylcellulose, hydroxypropylmethylcellulose, methylcellulose,and methoxycellulose. Exemplary synthetic polymers includepolyphosphazenes, polyethylenes (such as, for example, polyethyleneglycol (including the class of compounds referred to as Pluronics®,commercially available from BASF, Parsippany, N.J.), polyoxyethylene,and polyethylene terephthlate), polypropylenes (such as, for example,polypropylene glycol), polyurethanes, polyvinyl alcohol (PVA), polyvinylchloride and polyvinylpyrrolidone, polyamides including nylon,polystyrene, polylactic acids, fluorinated hydrocarbon polymers,fluorinated carbon polymers (such as, for example,polytetrafluoroethylene), acrylate, methacrylate, andpolymethylmethacrylate, and derivatives thereof.

The polymeric materials are selected from those materials which can bepolymerized or their viscosity altered in vivo by application ofexogenous means, for example, by application of light, ultrasound,radiation, or chelation, alone or in the presence of added catalyst, orby endogenous means, for example, a change to physiological pH,diffusion of calcium ions (alginate) or borate ions (polyvinyl alcohol)into the polymer, or change in temperature to body temperature (37° C.).

G. Agents that Promote Angiogenesis

One class of therapeutic agents to be encapsulated by the polymer fibersof the present invention are therapeutic agents that promoteangiogenesis. The successful engineering of new tissue requires theestablishment of a vascular network. The induction of angiogenesis ismediated by a variety of factors, any of which may be used inconjunction with the present invention (Folkman and Klagsbrun, 1987, andreferences cited therein, each incorporated herein in their entirety byreference). Examples of angiogenic factors includes, but is not limitedto: vascular endothelial growth factor (VEGF) or vascular permeabilityfactor (VPF); members of the fibroblast growth factor family, includingacidic fibroblast growth factor (aFGF) and basic fibroblast growthfactor (bFGF); interleukin-8 (IL-8); epidermal growth factor (EGF);platelet-derived growth factor (PDGF) or platelet-derived endothelialcell growth factor (PD-ECGF); transforming growth factors alpha and beta(TGF-α, TGF-β); tumor necrosis factor alpha (TNF-α); hepatocyte growthfactor (HGF); granulocyte-macrophage colony stimulating factor (GM-CSF);insulin growth factor-1 (IGF-1); angiogenin; angiotropin; angiotensin;fibrin and nicotinamide (Folkman, 1986, 1995; Auerbach and Auerbach,1994; Fidler and Ellis, 1994; Folkman and Klagsbrun, 1987; Nagy et al.,1995).

H. Cytokines

In certain embodiments the use of particular cytokines incorporated inthe polymer fibers of the present invention is contemplated. Table 2below is an exemplary, but not limiting, list of cytokines and relatedfactors contemplated for use in the present invention.

TABLE 2 Cytokine Reference Human IL-1 March et al., Nature, 315: 641,1985 Murine IL-1 Lomedico et al., Nature, 312: 458, 1984 Human IL-1March et al., Nature, 315: 641, 1985; Auron et al., Proc. Natl. Acad.Sci. U.S.A., 81: 7907, 1984 Murine IL-1 Gray, J. Immunol., 137: 3644,1986; Telford, NAR, 14: 9955, 1986 Human IL-1ra Eisenberg et al.,Nature, 343: 341, 1990 Human IL-2 Taniguchi et al., Nature, 302: 305,1983; Maeda et al., Biochem. Biophys. Res. Commun., 115: 1040, 1983Human IL-2 Taniguchi et al., Nature, 302: 305, 1983 Human IL-3 Yang etal., Cell, 47: 3, 1986 Murine IL-3 Yokota et al., Proc. Natl. Acad. Sci.U.S.A., 81: 1070, 1984; Fung et al., Nature, 307: 233, 1984; Miyatake etal., Proc. Natl. Acad. Sci. U.S.A., 82: 316, 1985 Human IL-4 Yokota etal., Proc. Natl. Acad. Sci. U.S.A., 83: 5894, 1986 Murine IL-4 Norma etal., Nature, 319: 640, 1986; Lee et al., Proc. Natl. Acad. Sci. U.S.A.,83: 2061, 1986 Human IL-5 Azuma et al., Nuc. Acids Res., 14: 9149, 1986Murine IL-5 Kinashi et al., Nature, 324: 70, 1986; Mizuta et al., GrowthFactors, 1: 51, 1988 Human IL-6 Hirano et al., Nature, 324: 73, 1986Murine IL-6 Van Snick et al., Eur. J. Immunol., 18: 193, 1988 Human IL-7Goodwin et al., Proc. Natl. Acad. Sci. U.S.A., 86: 302, 1989 Murine IL-7Namen et al., Nature, 333: 571, 1988 Human IL-8 Schmid et al., J.Immunol., 139: 250, 1987; Matsushima et al., J. Exp. Med. 167: 1883,1988; Lindley et al., Proc. Natl. Acad. Sci. U.S.A., 85: 9199, 1988Human IL-9 Renauld et al., J. Immunol., 144: 4235, 1990 Murine IL-9Renauld et al., J. Immunol., 144: 4235, 1990 Human Angiogenin Kurachi etal., Biochemistry, 24: 5494, 1985 Human GRO Richmond et al., EMBO J., 7:2025, 1988 Murine MIP-1 Davatelis et al., J. Exp. Med., 167: 1939, 1988Murine MIP-1 Sherry et al., J. Exp. Med., 168: 2251, 1988 Human MIFWeiser et al., Proc. Natl. Acad. Sci. U.S.A., 86: 7522, 1989 Human G-CSFNagata et al., Nature, 319: 415, 1986; Souza et al., Science, 232: 61,1986 Human GM-CSF Cantrell et al., Proc. Natl. Acad. Sci. U.S.A., 82:6250, 1985; Lee et al., Proc. Natl. Acad. Sci. U.S.A., 82: 4360, 1985;Wong et al., Science, 228: 810, 1985 Murine GM-CSF Gough et al., EMBOJ., 4: 645, 1985 Human M-CSF Wong, Science, 235: 1504, 1987; Kawasaki,Science, 230; 291, 1985; Ladner, EMBO J., 6: 2693, 1987 Human EGF Smithet al., Nuc. Acids Res., 10: 4467, 1982; Bell et al., NAR, 14: 8427,1986 Human TGF- Derynck et al., Cell, 38: 287, 1984 Human FGF acidicJaye et al., Science, 233: 541, 1986; Gimenez- Gallego et al., Biochem.Biophys. Res. Commun., 138: 611, 1986; Harper et al., Biochem., 25:4097, 1986 Human-ECGF Jaye et al., Science, 233: 541, 1986 Human FGFbasic Abraham et al., EMBO J., 5: 2523, 1986; Sommer et al., Biochem.Biophys. Res. Comm., 144: 543, 1987 Murine IFN- Higashi et al., J. Biol.Chem., 258: 9522, 1983; Kuga, NAR, 17: 3291, 1989 Human IFN- Gray etal., Nature, 295: 503, 1982; Devos et al., NAR, 10: 2487, 1982;Rinderknecht, J. Biol. Chem., 259: 6790, 1984 Human IGF-I Jansen et al.,Nature, 306: 609, 1983; Rotwein et al., J. Biol. Chem., 261: 4828, 1986Human IGF-II Bell et al., Nature, 310: 775, 1984 Human-NGF chain Ullrichet al., Nature, 303: 821, 1983 Human NT-3 Huang EJ. Et al., Development.126(10): 2191– 203, 1999 May. Human PDGF A Betsholtz et al., Nature,320: 695, 1986 chain Human PDGF B Johnsson et al., EMBO J., 3: 921,1984; Collins et chain al., Nature, 316: 748, 1985 Human TGF-1 Deryncket al., Nature, 316: 701, 1985 Human TNF- Pennica et al., Nature, 312:724, 1984; Fransen et al., Nuc. Acids Res., 13: 4417, 1985 Human TNF-Gray et al., Nature, 312: 721, 1984 Murine TNF- Gray et al., Nucl. AcidsRes., 15: 3937, 1987 Human E-Selectin Bevilacqua el al., Science, 243:1160, 1989; Hensley et al., J. Biol. Chem., 269: 23949, 1994 HumanICAM-1 Simmons et al., Nature, 331: 624, 1988 Human PECAM Simmons etal., J. Exp. Med., 171: 2147, 1990 Human VCAM-1 Hession et al., J. Biol.Chem., 266: 6682; Osborn et al., Cell, 59: 1203, 1989 Human L-SelectinOrd et al., J. Biol. Chem., 265: 7760, 1990; (membrane bound) Tedder etal., J. Exp. Med., 170: 123, 1989 Human L-Selectin Ord et al., J. Biol.Chem., 265: 7760, 1990; (soluble form) Tedder et al., J. Exp. Med., 170:123, 1989 Human Calcitonin Le Moullec et al., FEBS Lett., 167: 93, 1984Human Hirudin (E. Dodt et al., FEBS Lett., 165: 180, 1984 colioptimized)

G. Polynucelotides

The polynucleotides to be incorporated within the polymer fibers of thepresent invention extend to the full variety of nucleic acid molecules.The nucleic acids thus include genomic DNA, cDNAs, single stranded DNA,double stranded DNA, triple stranded DNA, oligonucleotides, Z-DNA, mRNA,tRNA and other RNAs. DNA molecules are generally preferred, even wherethe DNA is used to express a therapeutic RNA, such as a ribozyme orantisense RNA.

A “gene” or DNA segment encoding a selected protein or RNA, generallyrefers to a DNA segment that contains sequences encoding the selectedprotein or RNA, but is isolated away from, or purified free from, totalgenomic DNA of the species from which the DNA is obtained. Includedwithin the terms “gene” and “DNA segment”, are DNA segments and smallerfragments of such segments, and also recombinant vectors, including, forexample, plasmids, cosmids, phage, retroviruses, adenoviruses, and thelike.

The term “gene” is used for simplicity to refer to a functional proteinor peptide encoding unit. As will be understood by those in the art,this functional term includes both genomic sequences and cDNA sequences.“Isolated substantially away from other coding sequences” means that thegene of interest forms the significant part of the coding region of theDNA segment, and that the DNA segment does not contain large portions ofnaturally-occurring coding DNA, such as large chromosomal fragments orother functional genes or cDNA coding regions. Of course, this refers tothe DNA segment as originally isolated, and does not exclude genes orcoding regions, such as sequences encoding leader peptides or targetingsequences, later added to the segment by the hand of man.

The present invention does not require that highly purified DNA orvectors be used, so long as any coding segment employed encodes aselected protein or RNA and does not include any coding or regulatorysequences that would have a significant adverse effect on the targetcells. Therefore, it will also be understood that useful nucleic acidsequences may include additional residues, such as additional non-codingsequences flanking either of the 5′ or 3′ portions of the coding regionor may include various internal sequences, i.e., introns, that are knownto occur within genes.

Many suitable DNA segments may be obtained from existing, includingcommercial sources. One may also obtain a new DNA segment encoding aprotein of interest using any one or more of a variety of molecularbiological techniques generally known to those skilled in the art. Forexample, cDNA or genomic libraries may be screened using primers orprobes with designed sequences. Polymerase chain reaction (PCR) may alsobe used to generate a DNA fragment encoding a protein of interest.

After identifying an appropriate selected gene or DNA molecule, it maybe inserted into any one of the many vectors currently known in the art,so that it will direct the expression and production of the selectedprotein when incorporated into a target cell. In a recombinantexpression vector, the coding portion of the DNA segment is positionedunder the control of a promoter/enhancer element. The promoter may be inthe form of the promoter that is naturally associated with a selectedgene, as may be obtained by isolating the 5′ non-coding sequenceslocated upstream of the coding segment or exon, for example, usingrecombinant cloning and/or PCR technology.

In other embodiments, it is contemplated that certain advantages will begained by positioning the coding DNA segment under the control of arecombinant, or heterologous, promoter. As used herein, a recombinant orheterologous promoter is intended to refer to a promoter that is notnormally associated with a selected gene in its natural environment.Such promoters may include those normally associated with other selectedgenes, and/or promoters isolated from any other bacterial, viral,eukaryotic, or mammalian cell. Naturally, it will be important to employa promoter that effectively directs the expression of the DNA segment inthe chosen target cells.

The use of recombinant promoters to achieve protein expression isgenerally known to those of skill in the art of molecular biology, forexample, see Sambrook et al (1989; incorporated herein by reference).The promoters employed may be constitutive, or inducible, and can beused under the appropriate conditions to direct high level or regulatedexpression of the introduced DNA segment. Expression of genes under thecontrol of constitutive promoters does not require the presence of aspecific substrate to induce gene expression and will occur under allconditions of cell growth. In contrast, expression of genes controlledby inducible promoters is responsive to the presence or absence of aninducing agent.

Promoters isolated from the genome of viruses that grow in mammaliancells, e.g., RSV, vaccinia virus 7.5K, SV40, HSV, adenoviruses MLP, MMTVLTR and CMV promoters, may be used herewith, as well as promotersproduced by recombinant DNA or synthetic techniques. Currently preferredpromoters are those such as CMV, RSV LTR, the SV40 promoter alone, andthe SV40 promoter in combination with the SV40 enhancer.

Exemplary tissue specific promoter/enhancer elements and transcriptionalcontrol regions that exhibit tissue specificity include, but are notlimited to: the elastase I gene control region that is active inpancreatic acinar cells; the insulin gene control region that is activein pancreatic cells; the immunoglobulin gene control region that isactive in lymphoid cells; the albumin, 1-antitrypsin and -fetoproteingene control regions that are active in liver; the -globin gene controlregion that is active in myeloid cells; the myelin basic protein genecontrol region that is active in oligodendrocyte cells in the brain; themyosin light chain-2 gene control region that is active in skeletalmuscle; and the gonadotropic releasing hormone gene control region thatis active in the hypothalamus.

Specific initiation signals may also be required for sufficienttranslation of inserted protein coding sequences. These signals includethe ATG initiation codon and adjacent sequences. In cases where theentire coding sequence, including the initiation codon and adjacentsequences are inserted into the appropriate expression vectors, noadditional translational control signals may be needed. However, incases where only a portion of the coding sequence is inserted, exogenoustranslational control signals, including the ATG initiation codon shouldbe provided. The initiation codon must be in phase with the readingframe of the protein coding sequences to ensure translation of theentire insert. These exogenous translational control signals andinitiation codons can be of a variety of origins, both natural andsynthetic. The efficiency and control of expression may be enhanced bythe inclusion of transcription attenuation sequences, enhancer elements,etc.

A variety of vectors may be used including, but not limited to, thosederived from recombinant bacteriophage DNA, plasmid DNA or cosmid DNA.For example, plasmid vectors such as pBR322, pUC 19/18, pUC 118, 119 andthe M13 mp series of vectors may be used. Bacteriophage vectors mayinclude gt10, gt11, gt18–23, ZAP/R and the EMBL series of bacteriophagevectors. Cosmid vectors that may be utilized include, but are notlimited to, pJB8, pCV 103, pCV 107, pCV 108, pTM, pMCS, pNNL, pHSG274,COS202, COS203, pWE15, pWE16 and the charomid 9 series of vectors.Vectors that allow for the in vitro transcription of RNA, such as SP6vectors, may also be used to produce large quantities of RNA that may beincorporated into matrices.

The selected genes and DNA segments may also be in the form of a DNAinsert located within the genome of a recombinant virus, such as, forexample a recombinant herpes virus, retroviruses, vaccinia viruses,adenoviruses, adeno-associated viruses or bovine papilloma virus. Whileintegrating vectors may be used, non-integrating systems, which do nottransmit the gene product to daughter cells for many generations willoften be preferred. In this way, the gene product is expressed during adefined biological process, e.g., a wound healing process, and as thegene is diluted out in progeny generations, the amount of expressed geneproduct is diminished.

In such embodiments, to place the gene in contact with a target cell,one would prepare the recombinant viral particles, the genome of whichincludes the gene insert, and contact the target cells or tissues viarelease from the polymer fiber of the present invention, whereby thevirus infects the cells and transfers the genetic material.

Genes with sequences that vary from those described in the literatureare also contemplated for use in the invention, so long as the alteredor modified gene still encodes a protein that functions to effect thetarget cells in the desired (direct or indirect) manner. These sequencesinclude those caused by point mutations, those due to the degeneraciesof the genetic code or naturally occurring allelic variants, and furthermodifications that have been introduced by genetic engineering, i.e., bythe hand of man.

Techniques for introducing changes in nucleotide sequences that aredesigned to alter the functional properties of the encoded proteins orpolypeptides are well known in the art. Such modifications include thedeletion, insertion or substitution of bases, and thus, changes in theamino acid sequence. Changes may be made to increase the activity of aprotein, to increase its biological stability or half-life, to changeits glycosylation pattern, confer temperature sensitivity or to alterthe expression pattern of the protein, and the like. All suchmodifications to the nucleotide sequences are encompassed by thisinvention.

It is an advantage of the present invention that one or more than oneselected gene may be used in the gene transfer methods and compositions.The nucleic acid delivery methods may thus entail the administration ofone, two, three, or more, selected genes. The maximum number of genesthat may be applied is limited only by practical considerations, such asthe effort involved in simultaneously preparing a large number of geneconstructs or even the possibility of eliciting an adverse cytotoxiceffect. The particular combination of genes may be chosen to alter thesame, or different, biochemical pathways. For example, a growth factorgene may be combined with a hormone gene; or a first hormone and/orgrowth factor gene may be combined with a gene encoding a cell surfacereceptor capable of interacting with the polypeptide product of thefirst gene.

In using multiple genes, they may be combined on a single geneticconstruct under control of one or more promoters, or they may beprepared as separate constructs of the same of different types. Thus, analmost endless combination of different genes and genetic constructs maybe employed. Certain gene combinations may be designed to, or their usemay otherwise result in, achieving synergistic effects on cellstimulation and tissue growth, any and all such combinations areintended to fall within the scope of the present invention. Indeed, manysynergistic effects have been described in the scientific literature, sothat one of ordinary skill in the art would readily be able to identifylikely synergistic gene combinations, or even gene-protein combinations.

It will also be understood that, if desired, the nucleic segment or genecould be administered in combination with further agents, such as, e.g.proteins or polypeptides or various pharmaceutically active agents. Solong as genetic material forms part of the composition, there isvirtually no limit to other components which may also be included, giventhat the additional agents do not cause a significant adverse effectupon contact with the target cells or tissues. The nucleic acids maythus be delivered along with various other agents, for example, incertain embodiments one may wish to administer an angiogenic factor asdisclosed in U.S. Pat. No. 5,270,300 and incorporated herein byreference.

As the chemical nature of genes, i.e., as a string of nucleotides, isessentially invariant, and as the process of gene transfer andexpression are fundamentally the same, it will be understood that thetype of genes transferred by the fiber matrices of the present inventionis virtually limitless. This extends from the transfer of a mixture ofgenetic material expressing antigenic or immunogenic fragments for usein DNA vaccination; to the stimulation of cell function, as inwound-healing; to aspects of cell killing, such as in transferring tumorsuppressor genes, antisense oncogenes or apoptosis-inducing genes tocancer cells.

By way of example only, genes to be supplied by the invention include,but are not limited to, those encoding and expressing: hormones, growthfactors, growth factor receptors, interferons, interleukins, chemokines,cytokines, colony stimulating factors and chemotactic factors;transcription and elongation factors, cell cycle control proteins,including kinases and phosphatases, DNA repair proteins,apoptosis-inducing genes; apoptosis-inhibiting genes, oncogenes,antisense oncogenes, tumor suppressor genes; angiogenic andanti-angiogenic proteins; immune response stimulating and modulatingproteins; cell surface receptors, accessory signaling molecules andtransport proteins; enzymes; and anti-bacterial and anti-viral proteins.

H. Kits

All the essential materials and reagents required for the variousaspects of the present invention may be assembled together in a kit. Thekits of the present invention also will typically include a means forcontaining the vials comprising the desired components in closeconfinement for commercial sale such as, e.g., injection or blow-moldedplastic containers into which the desired vials are retained.Irrespective of the number or type of containers, the kits of theinvention are typically packaged with instructions for use of the kitcomponents.

WORKING EXAMPLES

The following examples are included to demonstrate preferred embodimentsof the invention and are not intended to limit the scope of theinvention in any way. It should be appreciated by those of skill in theart that the techniques disclosed in the examples which follow representtechniques discovered by the inventor to function well in the practiceof the invention, and thus can be considered to constitute preferredmodes for its practice. However, those of skill in the art should, inlight of the present disclosure, appreciate that many changes can bemade in the specific embodiments which are disclosed and still obtain alike or similar result without departing from the spirit and scope ofthe invention.

Example 1 Extrusion of Gel or Hydrogel Bored Fibers

In one embodiment of the present invention, the following procedure isused to create gel or hydrogel bored drug-releasing fibers. Theapparatus used is depicted in FIG. 7, which details a fiber spinneret inwhich a coagulant bore fluid is fed through a small diameter hypodermictube, which is centered in a blunt-end hypodermic needle. However, anysimilar configuration including scaled-up versions and specificallybuilt apparatus' are included within the scope of the invention. Thisconfiguration allows for an annulus of polymer to flow through thespinneret, bored by a water-based gel or hydrogel. First, abiodegradable polymer such as poly(L-lactic acid) (PLLA), poly(DL-lacticacid), polycaprolactone, poly(glycolic acid), polyanhydride, orcopolymers or blends of these or other biodegradable polymers isdissolved in some appropriate solvent (A) at concentrations ranging from5 to 30 wt % depending on the type of polymer, 10 wt % being preferredfor PLLA at 200 kD molecular weight. In this embodiment, solvent (A) haslow miscibility with water, and is very miscible with the coagulationbath solvent (B), but not with the water in the gel or hydrogel in thebore. The water does not function as a solvent or non-solvent in thisapplication. Preferred choices of solvent (A) include chloroform andmethylene chloride. Once the polymer is dissolved in the chosen solvent,a non-solvent (solvent C) is typically added to the polymer solution inan appropriate concentration to reduce the solvation power of thesolvent system, yet not bring the solution to its cloud point. Thisnon-solvent is highly miscible with solvent (A), and with solvent (B),and in some cases may be the same as solvent (B). Typical choicesinclude iso-octane, cyclohexane, and hexane. This non-solvent brings thepolymer in the solution close to its cloud point, so that the solutionwill more quickly precipitate to form a fiber when extruded into thecoagulant bath, solvent (B).

The gel or hydrogel is prepared using standard procedures known to thosewho practice the art. As an example, for an internally gelled alginatebore fluid, sodium alginate powder is first dissolved indistilled-deionized water to yield a concentration in the range of 0.5to 50 wt %, with 1 wt % being desired for this-example. Once dissolved,the solution is sterile filtered to provide an appropriate stock for thegel extrusion process. To promote internal gelation of the alginate, anappropriate quantity of calcium carbonate, CaCO₃, is added to thesolution and mixed thoroughly by vortexing, sonicating, or homogenizing.Calcium carbonate is not soluble in water at neutral pH, so the powderultimately is suspended in the alginate solution. To this solution, anappropriate quantity of D-Glucono-delta-Lactone (GDL) is added to slowlydrop the solution pH, which initiates liberation of free Ca⁺⁺ from theCaCO₃ to cross-link the guluronic acid residues in the alginate, thusforming a hydrogel. The rate of gelation and the properties of the gelcan be controlled through the concentration of CaCO₃ and the ration ofGDL to CaCO₃ used in the solution.

The prepared gel solution and the polymer solution are then immediatelyextruded into the coagulating bath containing solvent (B), through thespinneret device depicted in FIG. 8, such that the polymer flows arounda center tube containing the gel or hydrogel and, if desired, a drug ofchoice either dissolved in the gel, or encapsulated in nanospheres orliposomes and suspended in the gel. The polymer solution and gel orhydrogel core are extruded into the coagulation bath through a spinneretaccording to the size of the desired fiber, as these fibers are nottypically drawn, the final fiber size is close to the spinneret size.The optimum ration of outer annulus to inner gel or hydrogel diameterneeds to be experimentally determined. For example, to obtain fiberswhose outer diameter are approximately 500 μm, the inventor's laboratoryhas used an outer lumen of 18 gage with a 24 or 25 gage inner lumen forthe bore fluid. Any water-based gel, precursor hydrogel component, orhydrogel can be delivered through the center tube. Frequently, the innergel or hydrogel is carrying a drug that is incompatible with organicsolvents, or the gel or hydrogel does not tolerate the presence oforganic solvents. Therefore, it is generally preferred that the solventfor the gel or hydrogel (generally water) is immiscible with solvents(A), (B) and (C). Solvent (B) must be highly miscible with solvents (A)and (C), immiscible with the water component of the bore fluid, and mustbe a non-solvent for the polymer; hexane and pentane are the mosttypical choices, but any solvent that meets the above criteria andquickly draws the solvent from the polymer solution will theoreticallywork. Wherefore, chloroform and pentane make a good solvent andcoagulating bath combination with iso-octane as the added non-solvent.Because solvent (A) is highly miscible with coagulating bath solvent(B), it freely diffuses from the polymer solution stream into thecoagulating bath, reducing the solvent power of the polymer solutionbelow the cloud point, which causes the polymer to begin to precipitateto form a solid polymer sheath. Occasionally, the polymer sheath mustbegin to precipitate and form before it is subjected to the stress ofbeing exposed to the gel or hydrogel flowing in the inner lumen. Thisrequires that the axial positions of the inner lumen protrude below theoutlet of the outer annulus (0–2 mm typical in inventor's laboratory) toensure that the polymer solution is exposed to the coagulant bath justprior to the gel or hydrogel bore fluid contacting the polymer. Thenon-solvent (C), incorporated into the polymer solution accelerates theprecipitation process. As neither solvent (A) nor (B) freely diffuseinto the bore fluid, only a single coagulant front is created as thepolymer exits the spinneret, thereby encapsulating the bore gel orhydrogel. The distance the fiber drops into the coagulating bath isimportant to the formation of the fiber and its ultimate properties, andis typically 10–30 cm. In the inventor's laboratory, the fiber has beenallowed to freely Call and collect at the bottom of the coagulating bathcontainer; however, other designs including drawing the fiber out of thecoagulating bat are included as part of this invention. The extrudedfiber may be post-processed and stored in a number of ways includingfreeze-dried, frozen, or oven dried and placed in a desecrator orfreezer, depending upon recommended storage conditions of the loadedbiomolecules and the properties of the gel or hydrogel.

Example 2 Extrusion of a Gel Coated Polymer Fiber

In another embodiment of the present invention, a PLLA or otherbiodegradable polymer fiber coated with a hydrogel is created. Theextrusion process is similar to that described, except the coagulantbath used contains a coagulant or crosslinker for the hydrogel. Thepolymer and hydrogel are extruded through a spinneret similar to thatpreviously described, with the polymer solution (possibly containing adrug in a dispersed aqueous or gel phase) extruded through the innerbore of the spinneret and the gel or hydrogel (possibly containing adrug) solution extruded through the outer annulus of the spinneret. Thesolutions are prepared as described or as otherwise known to those whopractice the art, and are extruded at the same time through thespinneret. In the case of a dual lumen spinneret, the polymer solutionis extruded without direct exposure to a coagulant. In this case, thepolymer solvent must be removed by a post-processing step, or if thereare no reasons to the contrary, the coagulating bath may contain amixture of solvents, at least one of which miscible with both water andthe polymer solvent; examples of which include isopropyl alcohol,acetone etc. This will allow the polymer solvent (typically chloroformor methylene chloride) to leave through the gel or hydrogel exteriorlayer being carried by the water miscible solvent. The coagulant bathalso contains a solution known to those who practice the art thatcrosslinks or otherwise forms the gel or hydrogel. In the case ofalginate hydrogel, the coagulant bath can be an appropriateconcentration solution of CaCl₂ in water. As the polymer solution, andalginate solution flow from the spinneret, the alginate solution (whichcould contain CaCO₃ and GDL as noted above) contacts the coagulant andis crosslinked by calcium ions in the solution. If a polymer coagulantis used, solvent in the polymer/emulsion will diffuse into the coagulantand the polymer will form a fiber. If no coagulant is used, the polymersolution will be encapsulated by the rapidly crosslinking alginatesolution such that an alginate shelled fiber will form. The residualsolvent within the polymer can be removed by appropriate post-processingtechniques.

Example 3 Extrusion of Gel or Hydrogel Exterior Hollow Fibers Using aCoagulant Bore Fluid

In one embodiment of the present invention, the following procedure isused to create gel or hydrogel exterior, hollow fibers. The apparatusincludes a triple lumen spinneret, which also implies three pumps. Thecoagulant bath consists of a glass tube mounted vertically with one endimmersed into reservoir of coagulant bath consists of a glass tubemounted vertically with one end immersed into a reservoir of coagulantfluid, and the other end sealed with a septum. Coagulant is drawn intothe tube from the reservoir by piercing the septum with a needle andextracting the air in the tube with a large volume syringe. When filled,the syringe needle is removed and the septum seals the tube. As inexample 2, the coagulant must include a means of gelling the exteriorlayer of gel or hydrogel. Again, in the case of alginate for example, asolution of calcium chloride may be appropriate. The gel or hydrogelsolution flows through the outermost lumen, the biodegradable polymerthrough the inner lumen, and a coagulant for the polymer as definedabove, flows through the innermost lumen. The fiber is drawn from thecoagulation bath at a determined rate. In the laboratory, the inventorshave used a cylinder attached to a modified variable-speed lathe thatcan accurately maintain its angular velocity. The drawn and extrudedfiber is then removed from the cylinder and coagulant in the center ofthe fiber without collapsing the fiber. Residual coagulant and water areremoved by freeze-drying, freezing or oven drying the fiber and placingit into a desecrator or freezer, depending upon recommended storageconditions.

Example 4 Extrusion of Hollow Fibers Using Water as a Bore Fluid (WaterBore Fiber)

In one embodiment of the present invention, the following procedure isused to create water-bored drug-released fibers. The apparatus issimilar to that used in Example 1. This configuration allows for anannulus of polymer to flow through the spinneret, bored by a water-basedfluid. First, a biodegradable polymer such as poly(L-lactic acid)(PLLA), poly(DL-lactic acid), polycaprolactone, poly(glycolic acid),polyanhydride, or copolymers or blends of these or other biodegradablepolymers is dissolved in some appropriate solvent (A) at concentrationsranging from 5 to 30 wt % depending on the type of polymer, 10 wt %being preferred for PLLA at 200 kD molecular weight. In this embodiment,solvent (A) has low miscibility with water, and is very miscible withthe coagulation bath solvent (B), but not with the water in the bore.The water does not function as a solvent or non-solvent in thisapplication. Preferred choices of solvent (A) include chloroform andmethylene chloride. Once the polymer is dissolved in the chosen solvent,a non-solvent is added to the polymer solution in an appropriateconcentration to reduce the solvating power of the solvent system of thepolymer, yet not bring the solution to its cloud point. This non-solvent(solvent C) is highly miscible with solvent (A), and with solvent (B).Typical choices include iso-octane, cyclohexane, and hexane. Thisnon-solvent brings the polymer in the solution close to its point ofcoagulation, so that the solution will more quickly form a fiber whenextruded into the coagulant bath.

The polymer solution is then extruded into a coagulating bath containingsolvent (B), though a spinneret device such that the polymer flowsaround a center tube containing water and, if desired, a drug of choiceeither dissolved in the water, or encapsulated in nanospheres orliposomes and suspended in the water. The polymer solution is extrudedinto the coagulation bath through a dispensing tip ranging in size from16 gage down to 27 gage, with the hypodermic tubing containing the waterbore fluid appropriately sized to fit within the chosen dispensing tip.Any water-based fluid can be delivered through the center tube, providedthis solution is immiscible with solvent (A). Solvent (B) must be highlymiscible with solvents (A) and (C), and must be a non-solvent for thepolymer; hexane and pentane are the most typical choices, but anysolvent that is a non-solvent for the polymer and highly miscible withsolvents (A) and (C) will work for this application, provided it quicklydraws the solvent from the polymer solution. For example pentane is verymiscible with chloroform and iso-octane, yet is a non-solvent for thepolymer. Therefore, chloroform, iso-octane and pentane make a goodsolvent, non-solvent, and coagulating bath combination. Because solvent(A) is highly miscible with coagulating bath solvent (B), it freelydiffuses from the polymer solution stream into the coagulating bath. Therelative axial positions of the inner hypodermic tubing and thedispensing tip are adjusted to assure the annulus of polymer solution isexposed to the coagulant bath prior to the water bore contacting thepolymer. The non-solvent incorporated into the polymer solutionaccelerates the precipitation process, such that a shell is formed inthe polymer that entraps the bore solution. Neither solvent (A) nor (C)freely diffuse into the bore fluid, so only a single coagulant front iscreated as the polymer exits the spinneret. Additionally, theimmiscibility of the solvents with the bore protects it and itscontents. The coagulant bath used for this application consists of a 250ml or greater flask into which the fiber is allowed to drop and spool asit coagulates. The height of the drop is important to the formation ofthe fiber, and is typically 10–30 cm. The extruded fiber is removed fromthe flask and either freeze-dried, frozen, or oven dried and placed in adesecrator or freezer, depending upon recommended storage conditions.

Example 5 Alternate Fabrication Technique for Example 1, for HydrophilicFiber

The only difference is to use as a coagulating bath a molecule such aspoly(ethylene glycol) (PEG) of low molecular weight (in the range of 200to 600 Daltons is typical). This polymer is miscible with chloroform andmethylene chloride, yet a non-solvent for the polymer, such as PLLA.Therefore, it qualifies as a coagulation bath, however, this uniquecoagulating bath creates an interpenetrating network of PEG in the wallof the fiber, making them hydrophilic upon exposure to an aqueousenvironment. This can have interesting implications for implantation andmay alter cellular response to the fibers.

Example 6 Neural Tissue Engineering

In this aspect of the present invention, parallel arrays of fibers arepacked into tubes and loaded with neurotrophins for axonal growth. Thetube may be a very large version of a fiber of composition claimed inthis invention, wherein the gel or hydrogel core may have aconcentration of zero, or alternatively, be designed with an outersheath of gel or hydrogel, with a multi-component inner core of gel orhydrogel with an intermediate layer consisting of biodegradable polymer.The innermost gel or hydrogel may have a concentration of zero, and thebiodegradable polymer layer may be loaded with therapeutic agents eitherin a dispersed phase or directly mixed with the polymer. The exteriorgel or hydrogel may also contain therapeutic agents as may the interiorgel or hydrogel. Within the tube is a parallel array of fibers, whosecomposition may or may not be described by this invention or our priorinvention. For this example, at least one component, either the tube, orat least one fiber must be of a composition as described in thisinvention. This array of fibers inside the tube is placed in severedperipheral or central nerves. The therapeutic agents may be loaded in alinear or some other appropriate gradient in every element of the devicein which they are loaded (the exterior gel or hydrogel of the tube, theintermediate biodegradable polymer layer, or the innermost core of thetube, as well as the individual fibers within the tube in any and allpossible constituents as described herein), but the gradient can differin every occurrence within the device as desired. This device isimplanted bridging the gap between the ends of the nerve stumps. As thedevice releases its therapeutic agents, which may consist ofneurotrophins, anti-inflammatory agents, angiogenic factors, specificchemotactic or chemorepulsive agents etc., axons, vasculature, and othersupporting cells and tissues begin to migrate across the lesion. Oncethe axons reach the distal end, guidance cues are provided by existingSchwann or glial cells and reconnections can then be made. It has beenpreviously found that axons receive contact guidance by these fiberbundles and are able to traverse at least 1.8 cm in a rat sciatic nerveresection using non-loaded fibers. The optimal density of unloadedfibers in the tube is approximately 32 fibers in a 1.5 mm diameter tubefor rat sciatic nerve growth.

Example 7 Preparation and use of Polymer Fiber Stents

In another embodiment, fibers can be loaded with a drug of interest andused in stents or other medical devices where mechanical strength isrequired. The stents can be woven in such a manner as to have loadedfibers intermingled with unloaded fibers if needed for mechanicalproperties.

Fibers can also be used in conjunction with commercially availablestents to deliver drugs at the placement site. In this case, the fiberswould not provide any mechanical support, but would only serve as a drugdelivery reservoir.

Example 8 Preparation and use of Wound Dressings

In another embodiment, a gauze or dressing can be made from thesefibers. This dressing can have two sides, an upper surface that willrelease molecules for re-epithelialization and provide a substrate forthese cells. The bottom surface will promote regeneration of dermaltissue. This dressing is designed for dermal wound healing, includingburns, full thickness dermal wounds and chronic or non-healing woundsand sores. Each fiber can have multi-component, multi-layerconfiguration to provide temporal release of drugs or factors thatroughly correspond to the three phases of dermal wound healing.

As one example, in the case of a dressing designed for trauma patients,the first chemical to be released could be a pro-coagulant to help stopthe bleeding. The next layer could then release cytokines to helprecruit neutrophils and macrophages for the next phase of wound healing.Finally, a release of factors to help with reducing excessive scartissue and to inhibit contractions, which are particularly disabling toburn patients.

Example 9 Fabrication of Artificial Arteries

It may be possible to construct an artificial artery using techniquesdescribed herein. A series of hollow, concentric cylindrical sectionscan be knitted, woven, braided or fabricated using non-woven technologywith fibers loaded with various biological agents. The innermostcylinder is preferably tightly woven and contains drugs or agents topromote migrating, spreading and functioning of an intact endothelialcell layer. The next cylinder is composed of a woven or knittedarchitecture with fibers predominately circumferentially wound aroundthe inner cylinder. This layer will induce the migration andproliferation of smooth muscle fibers, and promote the expression ofelastin to create the internal elastic media. The next cylinder iscomposed of knitted or non-woven fibers and will contain drugs topromote the ingrowth of fibroblasts, macrophages and the creation ofextracellular matrix. The last layer will compose longitudinal fibersthat will promote the vascularization of the arterial cells via anartificial vasa vasorum, created by VEGF releasing fibers, or otherpromoters of angiogenesis.

Example 10 Drug Delivery Scaffold

In another application embodiment, these fibers can be used for drugdelivery scaffolds in places where a fiber format is appropriate. Forexample, inside the eye, where microspheres or other formats may be morelikely to interfere with the subject's vision, a fiber could be tackeddown and not float into the field of view. Fibers may be able to stay inplace better than microspheres or other formats such as nanoparticles,hydrogels, etc.

Example 11 Directed in situ Angiogenesis

In this embodiment, one or more fibers containing one or more of thefamily of angiogenic factors such as VEGF, bFGF, angiotensin or othersknown to induce angiogenesis are placed into the body along the pathwhere the directed angiogenesis is desired. As the fiber begins torelease the angiogenic factors endothelial cells from the surroundingvasculature will be induced to migrate out towards the fiber(s)following a process similar to normal angiogenesis. The fiber(s) usedmay have one or more of the compositions described in this invention, orit may be a tube with VEGF or similar growth factor that is chemotacticfor endothelial cells on the inside, and a different factor for smoothmuscles on the outside. In this way, the size of the created vessel maybe determined. In this application, cells are guided into initiallycell-free scaffoldings by cell-specific growth factors.

Example 12 Bone Fracture Healing

In another wound healing embodiment, proteins known to enhance bonefracture healing are loaded into a fiber. This fiber can then be wrappedaround the bone at the site of the fracture, releasing the growthfactors and enhancing the rate of fracture repair.

These fibers can either be in a helical structure (single or multiplehelix), or they may be woven into a loose, open weave. Either in thehelical or in the woven format, the fibers are placed around the bonefragments, holding them in place while releasing their growth factors.

In the case of a non-healing fracture that is due to lost or poor bloodsupply to the fracture site, a fiber or set of fibers containing VEGF orits equivalent may be used to enhance blood supply to the fracturedarea.

In this embodiment, bone fractures may be healed at accelerated ratescompared to non-treated fractures, and non-unions may be healed incertain cases.

In yet a third bone healing application, fibers releasing pain relievingdrugs may be used in the local area of the fracture. In this case, thefiber may be used in cases where plates, screws or other orthopedicdevices are implanted or other surgical manipulations of the bone areperformed. The local pain relief may lead the patient to apply load tothe fracture sooner and may lead to a stronger and more rapid mend, aswell as making life more comfortable for the patient.

Example 13 Skin Ulcer Healing

Similar to example 8 which described one form of dermal wound healing,another important example of this technology is the potential of healingchronic skin ulcers of various origins, such as diabetic foot ulcers,venous ulcers and general pressure sores. These conditions, andpotentially other similar conditions may be healed based on creating anon-woven mesh of fibers that release factors known to accelerate dermalwound healing, for example, platelet derived growth factor (PDGF),transforming growth factor-beta (TGF-beta), and VEGF or similar protein.This non-woven mesh can be inserted or packed directly into the ulcer orwound, where these growth factors can help accelerate the wound-healingprocess. These dressings can be designed for healing dermal sores andulcers. In this case, there is little need to reduce bleeding; ratherone of the biggest needs of these patients, particularly those withdiabetic ulcers is lack of blood supply to the wound site. Therefore,factors that induce angiogenesis may be able to increase circulation andhelp to rejuvenate the tissue at the site of the sore or ulcer.

Each dressing can be designed for the particular needs of the varioustypes of wounds or sores by altering the biomolecules that are released,and the kinetics at which they are released.

Example 14 Muscle Grafts

In another embodiment, parallel arrays of fibers may be loaded withmuscle stem cells. These stem cells can be of cardiac, smooth orskeletal muscle origin. Once these muscle stem cells are seeded onto thefiber array, the fibers can be mechanically stretched in vitro to helpthese cells align and differentiate properly. Alignment may also-beachieved by using fibers of very small diameter. Our experience withaxons indicates that with fibers on the order of 50 μm diameter tend tohelp cells align parallel to the axis of the fibers. Other fibers inthis bundle can release angiogenic factors to create a vascular supplyfor the muscle cells. In the case of skeletal or smooth muscle tissue,fibers for nerve growth can also be included to induce the formation ofneuromuscular junctions. Various experimental conditions used toharvest, isolate, reproduce and differentiate these stem cells are knownto those skilled in the art, and is not a part of this patent.

Example 15 Treatment of Glaucoma

Similar to drug delivery in the eye, described in example 10, and theneural stent described briefly in example 6, glaucoma may be treated bycombining an intraocular drug delivery with a neural treatment appliedto the optic nerve. Retinal ganglion cells undergo apoptosis leading todeath of the axons of the optic nerve. It is hypothesized that if thecells could be supported both within the eye as well as along the pathof the optic nerve, the cells may be able to survive. A fiber bundlethat releases growth factors such as NT-4, BDNF, CNTF, may be appliedtopically to the exterior of the optic nerve. Simultaneously, fibersthat release apoptosis inhibitors, or factors to support the retinalganglion cells are implanted within the eye. This combined effort mayprolong or save the sight of those suffering from glaucoma.

As is seen from the preceding examples, other tissues, organs, orstructures are possible to weave once the basic physiologic structure isunderstood. This can be extended to organs of the digestive system,musculoskeletal system, urological system, circulatory system, andnervous system.

Example 16 Creation of a Gel or Hydrogel Core in a Biodegradable PolymerSheath that Contains a Dispersed Aqueous Phase

In another embodiment of the invention, gel bored fibers may alsocontain therapeutic agents in a dispersed aqueous, gel or hydrogel phasewithin the biodegradable polymer fiber wall. The apparatus and extrusionconditions are similar to example 1 except as noted here.

Once the polymer is dissolved in solvent (A), an aqueous solution or agel or a hydrogel (including precursors) containing both thebiomolecules(s) of interest and a surfactant is added to the polymersolution. Additionally, a surfactant can be added to solvent (A). Theconcentration of the aqueous phase is typically in the range of 1 to 70%v/v of the polymer solution, 4–20% being most typical for gel orhydrogel filled PLLA fibers. The surfactant can be one or a combinationof substances familiar to those skilled in the art, such as bovine serumalbumin (BSA), poly(vinyl alcohol), pluronics, or biological surfactantssuch as the family of phospholipids. Other surfactants not specificallymentioned here, but known to those skilled in the art are included byextension. In a typical use, BSA is used as the surfactant atconcentrations ranging from about 10 fold to 100 fold higher than thebiological molecule of interest, with typical concentrations rangingfrom 2 wt % to 50 wt % of the aqueous phase. Note that the inventorsexperience has demonstrated that high protein concentrations aredifficult in the case of a gel or hydrogel, and therefore, thesurfactant of choice may depend on the type of the dispersed phase.

Using some form of mechanical energy such as sonication, vortexing, orshear forces generated by forcing the liquid through a small orifice, awater-in-oil type emulsion is formed between the aqueous and organicphases. Depending on the volume of aqueous solution relative to thepolymer solution, emulsification can be accomplished in stages, usingpartial additions of the aqueous phase until the total volume isincorporated into the polymer solution. This emulsion must be stable forperiods far in excess of time required for extrusion to insurehomogeneity of the emulsion throughout the extrusion process. The sizeof the dispersed aqueous phase droplets is primarily dependent on thequality of the surfactant, and the total amount of mechanical energyimparted to the system in forming the emulsion. The aqueous phase sizeis an important variable in both release kinetics and mechanicalproperties of the fiber. This emulsion is then used as the polymersolution, and all other details are the same as explained in example 1.

Example 17 Creation of a Gel or Hydrogel Exterior Fiber with aBiodegradable Polymer Fiber Core Containing a Dispersed Aqueous, Gel, orHydrogel Phase Within the Fiber Wall

This example is similar to example 2 in all details except that adispersed phase is added to the polymer solution as described in example16.

Example 18 Creation of a Gel or Hydrogel Exterior Hollow Fiber with aDispersed Gel or Hydrogel Phase Within the Fiber Wall

This example is similar to example 3 in all details except that adispersed phase is added to the polymer solution as described in example16.

Example 19 Creation of a Water-bore Fiber with a Dispersed Aqueous, Gelor Hydrogel Phase Within the Wall of the Fiber

This example is similar to example 4 in all details except that adispersed phase is added to the polymer solution as described in example16.

All of the compositions and methods disclosed and claimed herein can bemade and executed without undue experimentation in light of the presentdisclosure. While the compositions and methods of this invention havebeen described in terms of preferred embodiments, it will be apparent tothose of skill in the art that variations may be applied to thecompositions and methods and in the steps or in the sequence of steps ofthe method described herein without departing from the concept, spiritand scope of the invention. More specifically, it will be apparent thatcertain agents which are both chemically and physiologically related maybe substituted for the agents described herein while the same or similarresults would be achieved. All such similar substitutes andmodifications apparent to those skilled in the art are deemed to bewithin the spirit, scope and concept of the invention as defined by theappended claims.

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1. A drug delivery composition comprising at least one fiber having abore and a wall, wherein said fiber comprises a first component and asecond component, and wherein said first component is a biodegradablepolymer and said second component is selected from the group consistingof a gel and a hydrogel.
 2. The composition of claim 1 wherein saidfirst component is present in the fiber bore and said second componentis present in the fiber wall.
 3. The composition of claim 1 wherein saidsecond component is present in the fiber bore and said first componentis present in the fiber wall.
 4. The composition of claim 1 furthercomprising at least one additional fiber, wherein said additional fibercircumscribes an adjacent inner fiber.
 5. The composition of claim 4wherein said adjacent inner fiber is approximately centered within theouter fiber.
 6. The composition of claim 1, wherein a therapeutic agentis loaded into the gel or hydrogel.
 7. The composition of claim 6,wherein the therapeutic agent is a growth factor.
 8. The composition ofclaim 7, wherein said growth factor is a promoter of angiogenesis. 9.The composition of claim 7, wherein said growth factor promotes nerveregeneration.
 10. The composition of claim 6, wherein the therapeuticagent is a virus.
 11. The composition of claim 6, wherein thetherapeutic agent is selected from the group consisting of protein,enzymes, transcription factors, signaling molecules, internalmessengers, second messengers, kinases, proteases, cytokines,chemokines, structural proteins, interleukins, hormones,anti-coagulants, pro-coagulants, anti-inflammatory agents, antibiotics,agents that promote angiogenesis, agents that inhibit angiogenesis,growth factors, immunomodulators, chemotactic agents, agents thatpromote apoptosis, agents that inhibit apoptosis, and mitogenic agents.12. The composition of claim 1, wherein said gel or hydrogel is aprecursor gel or precursor hydrogel.
 13. The composition of claim 1,wherein said biodegradable polymer fiber comprises a hydrophobic drug.14. The composition of claim 1, wherein said gel or hydrogel comprises aradioactive material.
 15. A drug delivery composition comprising afiber, wherein said fiber comprises a first component and a secondcomponent, and wherein said first component is a biodegradable polymerand said second component is water, and further wherein said water ispresent as an inner core.
 16. The composition of claim 15 Anthercomprising at least one additional fiber, wherein said additional fibercircumscribes an adjacent inner fiber.
 17. The composition of claim 16wherein said adjacent inner fiber is approximately centered within theouter fiber.
 18. The composition of claim 15, wherein said biodegradablepolymer fiber comprises a hydrophobic drug.
 19. A drug deliverycomposition comprising a fiber, wherein said fiber comprises an emulsionconsisting essentially of a gel or hydrogel.
 20. A drug deliverycomposition comprising a fiber, wherein said fiber comprises a firstcomponent, and wherein said first component is a gel or hydrogel andfurther wherein said fiber comprises a hollow bore.
 21. A scaffoldcomposition comprising one or more fibers, wherein said fibers comprisea first component and a second component and wherein said firstcomponent is a biodegradable polymer and said second component isselected from the group consisting of a gel and a hydrogel.
 22. Thecomposition of claim 21 wherein said first component is present in thefiber bore and said second component is present in the fiber wall. 23.The composition of claim 21 wherein said second component is present inthe fiber bore and said first component is present in the fiber wall.24. The composition of claim 21 further comprising at least oneadditional fiber, wherein said additional fiber circumscribes anadjacent inner fiber.
 25. The composition of claim 24 wherein saidadjacent inner fiber is approximately centered within the outer fiber.26. The composition of claim 21, wherein therapeutic agent is loadedinto the gel or hydrogel.
 27. The composition of claim 26, wherein thetherapeutic agent is a growth factor.
 28. The composition of claim 27,wherein said growth factor is a promoter of angiogenesis.
 29. Thecomposition of claim 27, wherein said growth factor promotes nerveregeneration.
 30. The composition of claim 26, wherein the therapeuticagent is a virus.
 31. The composition of claim 26, wherein thetherapeutic agent is selected from the group consisting of protein,enzymes, transcription factors, signaling molecules, internalmessengers, second messengers, kinases, proteases, cytokines,chemokines, structural proteins, interleukins, hormones,anti-coagulants, pro-coagulant, anti-inflammatory agents, antibiotics,agents that promote angiogenesis, agents that inhibit angiogenesis,growth factors, immunomodulators, chemotactic agents, agents thatpromote apoptosis, agents that inhibit apoptosis, and mitogenic agents.32. The composition of claim 21, wherein said gel or hydrogel is aprecursor gel or precursor hydrogel.
 33. The composition of claim 21,wherein said biodegradable polymer fiber comprises a hydrophobic drug.34. The composition of claim 21, wherein said gel or hydrogel comprisesa radioactive material.